Pyrimidine compound and medicinal composition thereof

ABSTRACT

A compound having excellent adenosine receptor (A 1 , A 2A , A 2B  receptor) antagonistic action, of the following formula, a salt thereof or a solvate of them: 
                         
wherein, R 1  and R 2 , same or different, each represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, an aromatic hydrocarbon cyclic group, an acyl group or an alkylsulfonyl group, which groups may be substituted (except the hydrogen atom); R 3  represents a hydrogen atom, a halogen atom, a cyano group, an alkyl group, an alkenyl group, an alkynyl group, an aromatic hydrocarbon cyclic group, a nitrogen atom, an oxygen atom or a sulfur atom, which groups may be substituted (except the hydrogen atom, the halogen atom and the cyano group); R 4  represents an aromatic hydrocarbon cyclic group which may be substituted, and R 5  represents an aromatic hydrocarbon cyclic group which may be substituted.

FIELD OF THE INVENTION

The present invention relates to a novel pyrimidine compound, aproduction process thereof, and a pharmaceutical preparation containingit and use thereof.

PRIOR ART

Adenosine is an important regulatory factor involved in manyintracellular metabolisms in the living body such as regulation ofenergy levels, cAMP levels, opening and closing potassium channels, andinflow of calcium ions into cells, and its interaction with Gprotein-coupled adenosine receptors on the surface of a cell isessential for exhibiting these physiological activities. Adenosinereceptors were classified under two subtypes, A₁ receptor and A₂receptor based on the involvement in adenylate cyclase (J. Neurochem.,33, 999-1003, (1979)), and thereafter, the A₂ receptor has beenclassified under two subtypes, A_(2A) and A_(2B), based on the affinityfor A₂ receptor agonists, NECA and CGS-21680 (Mol. Pharmacol., 29,331-346, (1986); J. Neurochem., 55, 1763-1771, (1990)). Four receptorsubtypes, A₁, A₂ (A_(2A) and A_(2B)) and A₃, have been identified untilnow. The A₁ receptor is a protein coupled with G_(i/o) family proteins.It serves to inhibit the adenylate cyclase as a result of binding with aligand to thereby decrease the cAMP level and serves to activatephospholipase C (PLC) to thereby promote the production ofinositol-1,4,5-triphosphate (IP₃) and to release the intracellularcalcium ions. The A₃ receptor is a receptor serving to decrease the cAMPlevel and to activate PLC to thereby promote the IP₃ production and therelease of calcium ions, as the A₁ receptor. In contrast, the A_(2A) andA_(2B) receptors are receptors serving to activate the adenylate cyclaseand promote the production of cAMP. There is a report that the A_(2B)receptor couples with PLC via a G_(q)/G₁₁ protein or promotes theproduction of IP₃ and the flow of calcium ions into cells (J. din.Invest., 96, 1979-1986 (1995)). These subtypes are different from oneanother in their distribution in tissues; that is, the A₁ receptoroccurs relatively abundantly, for example, in the heart, aorta andbladder, the A_(2A) receptor is distributed relatively abundantly, forexample, in the eyeballs and skeletal muscles, the A₃ receptor, forexample, in the spleen, uterus, and prostate, and the A_(2B) receptor,for example, in the proximal colon, and subsequently in the eyeballs,lung, uterus and bladder (Br. J. Pharmacol., 118, 1461-1468 (1996)). Itis believed that these adenosine receptor subtypes can exhibit specificfunctions, respectively, due to the difference in distribution in thetissues as well as the difference in adenosine level among the locationsand the difference in affinity for the ligand among the subtypes.Adenosine is involved in a variety of physiological functions such asplatelet aggregation, heart rate, smooth muscle tonus, inflammation,release of neurotransmitters, neurotransmission, hormone release,cell-differentiation, cell growth, cell death, and DNA biosynthesis.Accordingly, the relation between adenosine and diseases such as centralnervous system diseases, cardiovascular diseases, inflammatory diseases,respiratory diseases, and immune diseases has been suggested, and theefficacy of agonists/antagonists of the adenosine receptors on thesediseases has been expected. Antagonists against the adenosine receptors,particularly those against the adenosine A₂ receptor have been discussedas effective as an agent for treating or preventing diabetes mellitus,diabetic complications, diabetic retinopathy, obesity or asthma and havebeen expected useful as, for example, a hypoglycemic agent, an agent forimproving glucose intolerance, an insulin sensitizer, a hypotensiveagent, a diuretic agent, an antidepressant, an agent for treatingosteoporosis, an agent for treating Parkinson's disease, an agent fortreating Alzheimer's disease, an agent for treating an inflammatorybowel disease, or an agent for treating Crohn's disease.

Certain important reports have been made on the relation between theadenosine A2 receptor and the intestinal tract. For example, certainreports have been made that the A2 receptor mediates a colonlongitudinal muscle relaxation action (Naunyn-Schmiedeberg's Arch.Pharmacol., 359, 140-146 (1999)), and that the A₁ receptor, and theA_(2B) receptor occurring in the longitudinal muscle mediate arelaxation action of adenosine against the contraction of distal colonlongitudinal muscle of a guinea pig (Br. J. Pharmacol., 129, 871-876(2000)). Such A_(2B) receptor antagonists do not induce diarrhea, havean excellent defecation-promoting action and are expected as an agentfor treating and/or preventing various constipation. They are alsoexpected as being useful for treating and/or preventing irritable bowelsyndrome, constipation accompanying irritable bowel syndrome, organicconstipation or constipation accompanying enteroparalytic ileus and forevacuating intestinal tracts at the time of examination of digestivetracts or before and after an operation.

Furthermore, in the formation of clinical condition of Parkinson'sdisease, it has been importantly reported that, adenosine is extremelyclosely involved through the adenosine A_(2A) receptor in addition todopamine. For instance, it has been reported that the effects forimproving the symptoms of Parkinson's disease will be enhanced by use ofL-DOPA together with theophylline which is known as a non-selectiveadenosine receptor antagonist (J. Pharm. Pharmacol., 46, 515-517,(1994)). Also, it has been reported that selective adenosine A_(2A)receptor antagonists are effective to various kinds of Parkinson'sdisease animal models (JP 1994-211856 A). Parkinson's disease is causedby the degradation or death of dopaminergic neurons projected from thecompact layer of midbrain substantia nigra to the corpus striatum.Although the progress of the disease cannot be prevented, thesymptomatic treatment with L-DOPA preparations is nevertheless afundamental treatment making up for a shortage to dompamine. However,the long-term usage of the L-DOPA preparations will reduce theeffectiveness thereof and produce some side effects such as involuntarymovements and mental symptoms. Therefore, the biggest problem is thatsufficient therapeutic effects cannot be attained by the L-DOPApreparations. The distribution of adenosine A_(2A) receptors in thebrain is confined in the corpus striatum, nucleus accumbens, andolfactory tubercle (Eur. J. Pharmacol., 168, 243-246 (1989)), SO thatthe adenosine A_(2A) receptors have been estimated to play an importantrole in motor function control in the corpus striatum. In addition, ithas been reported that the degradation of dopaminergic neurons in thecompact layer of midbrain substantia nigra does not affect the adenosineA_(2A) receptor binding ability of the corpus striatum and there is nodifference between Parkinson's disease subjects and normal healthysubjects with respect to the total number of adenosine A_(2A) receptors(Neuroscience, 42, 697-706, 1991). Recently, it has been also reportedthat selective adenosine A_(2A) receptor antagonists are harmless andimprove the motor functions of the subjects suffering from progressiveParkinson's disease without exaggerating dyskinesia with L-DOPApreparations (Neurology, 58 (suppl. 3) S21. 001 (2002.4)). As is evidentfrom these findings, it is expected that the adenosine A_(2A) receptorantagonists are useful as therapeutic agents for Parkinson's disease.

Following compounds have been reported as those having antagonisticaction on adenosine A_(2A) and/or adenosine A₂B receptors:

-   (1) Compounds represented by the following formulae:

-   (2) A purine derivative represented by the formula:

(wherein R¹ represents (1) the formula:

(wherein X represents a hydrogen atom, a hydroxyl group, a lower alkylgroup which may be substituted, a lower alkoxy group which may besubstituted, etc.; and R⁵ and R⁶ are the same as or different from eachother and each represents a hydrogen atom, a lower alkyl group which maybe substituted, a saturated or unsaturated cycloalkyl group having threeto eight carbon atoms which may be substituted, etc.) or (2) a 5 or6-membered aromatic ring which may have one or more substituents and ahetero atom; W represents the formula:—CH₂CH₂—, —CH═CH— or —C≡C—; R² represents an amino group which may besubstituted with a lower alkyl group which may be substituted, etc.; R³represents a cycloalkyl group having three to eight carbon atoms whichmay be substituted, an aryl group which may be substituted, etc.; and R⁴represents a lower alkyl group which may be substituted, etc.), apharmacologically acceptable salt thereof or a hydrate of them (JP-A11-263789).

-   (3) A purine compound represented by the formula:

(wherein R¹ represents a hydrogen atom, a hydroxyl group, a halogenatom, an alkyl group having one to eight carbon atoms which may besubstituted, etc.; R² represents an amino group which may be substitutedwith an alkyl group having one to eight carbon atoms, etc.; R³represents an alkynyl group having three to eight carbon atoms which maybe substituted with a halogen atom, a hydroxyl group or an alkyl grouphaving one to four carbon atoms, etc.; Ar represents an aryl group whichmay be substituted, a heteroaryl group which may be substituted, etc.;and Q and W are the same as or different from each other and eachrepresents N or CH), a pharmacologically acceptable salt thereof or ahydrate of them (JP-A 11-188484).

-   (4) A_(2B) receptor antagonists described in Drug Development    Research, 48: 95-103 (1999) and J. Med. Chem., 43: 1165-1172 (2000).-   (5) A_(2A) receptor antagonists represented by the following    formula:

(JP-A 6-211856).

As pyrimidine compounds, there are only reports relating to 5,6-aromaticsubstituted pyrimidine compounds in publications such as WO97/33883,WO98/24782 and WO99/65897. However, the relation between these compoundsand the adenosine receptors has been neither reported nor suggested andhas not yet been known.

As is described above, compounds having an adenosine receptorantagonism, among them, compounds having an adenosine A₂ receptorantagonism, that is, compounds having an A_(2A) and/or A_(2B) receptorantagonism are expected to exhibit an excellent action as a medicament,and strong demands have been made to provide such compounds. However,compounds which have an excellent antagonism against the adenosinereceptors and effectively act as a medicament have not yet been found.Accordingly, an object of the present invention is to search for andfind compounds which serve to inhibit the adenosine receptors (A_(2A)and A_(2B) receptors) and are useful as an agent for treating orpreventing a disease to which the adenosine receptors relate.

DISCLOSURE OF THE INVENTION

After intensive investigations under these circumstances, the presentinventors have succeeded, for the first time, to synthesize a compoundrepresented by the formula:

(in the formula, R¹ and R² are the same as or different from each otherand each represents a hydrogen atom, an alkyl group having one to sixcarbon atoms which may be substituted, an alkenyl group having two tosix carbon atoms which may be substituted, an alkynyl group having twoto six carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted, a 5 to 14-membered aromatic heterocyclic groupwhich may be substituted, an acyl group having one to six carbon atomswhich may be substituted or an alkylsulfonyl group having one to sixcarbon atoms which may be substituted; R³ represents a hydrogen atom, ahalogen atom, a cyano group, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, an aromatic hydrocarboncyclic group having six to fourteen carbon atoms which may besubstituted, a 5 to 14-membered aromatic heterocyclic group which may besubstituted, a nitrogen atom which may be substituted, an oxygen atomwhich may be substituted or a sulfur atom which may be substituted; R⁴represents an aromatic hydrocarbon cyclic group having six to fourteencarbon atoms which may be substituted, a 5 to 14-membered aromaticheterocyclic group which may be substituted or a 5 to 14-memberednon-aromatic heterocyclic group having at least one or more unsaturatedbonds which may be substituted; and R⁵ represents an aromatichydrocarbon cyclic group having six to fourteen carbon atoms which maybe substituted or a 5 to 14-membered aromatic heterocyclic group whichmay be substituted), a salt thereof or a solvate of them. They haveunexpectedly found that the compound, a salt thereof or a solvate themhave an excellent antagonism against the adenosine A₂ receptors, that isagainst the A_(2A) and/or A_(2B) receptor. After further intensiveinvestigations, they have found that the compound, a salt thereof or asolvate of them has a remarkable efficacy on diseases to which theadenosine receptors, particularly the adenosine A₂ receptors, furtherparticularly the adenosine A_(2A) and/or A_(2B) receptor relates, andthat it is efficacious for preventing and/or treating variousconstipation (constipation, irritable bowel syndrome, constipationaccompanying irritable bowel syndrome, organic constipation,constipation accompanying enteroparalytic ileus, constipationaccompanying congenital digestive tract dysfunction, or constipationaccompanying ileus) and is also useful as an agent for treating,preventing or improving, for example, diabetes mellitus, diabeticcomplications, diabetic retinopathy, obesity or asthma, and as ahypoglycemic agent, an agent for improving glucose intolerance, aninsulin sensitizer, a hypotensive agent, a diuretic agent, anantidepressant, an agent for treating osteoporosis, an agent fortreating Parkinson's disease, an agent for treating Alzheimer's disease,an agent for treating an inflammatory intestinal disease or an agent fortreating Crohn's disease. The present invention has been accomplishedbased on these findings.

That is, the present invention relates to (1) a compound represented bythe formula:

(in the formula, R¹ and R² are the same as or different from each otherand each represents a hydrogen atom, an alkyl group having one to sixcarbon atoms which may be substituted, an alkenyl group having two tosix carbon atoms which may be substituted, an alkynyl group having twoto six carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted, a 5 to 14-membered aromatic heterocyclic groupwhich may be substituted, an acyl group having one to six carbon atomswhich may be substituted or an alkylsulfonyl group having one to sixcarbon atoms which may be substituted; R³ represents a hydrogen atom, ahalogen atom, a cyano group, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, an aromatic hydrocarboncyclic group having six to fourteen carbon atoms which may besubstituted, a 5 to 14-membered aromatic heterocyclic group which may besubstituted, a nitrogen atom which may be substituted, an oxygen atomwhich may be substituted or a sulfur atom which may be substituted; R⁴represents an aromatic hydrocarbon cyclic group having six to fourteencarbon atoms which may be substituted, a 5 to 14-membered aromaticheterocyclic group which may be substituted or a 5 to 14-memberednon-aromatic heterocyclic group having at least one or more unsaturatedbonds which may be substituted; and R⁵ represents an aromatichydrocarbon cyclic group having six to fourteen carbon atoms which maybe substituted or a 5 to 14-membered aromatic heterocyclic group whichmay be substituted), a salt thereof or a solvate of them; (2) thecompound described in (1), a salt thereof or a solvate of them, whereinR¹ and R² are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted, a 5 to 14-membered aromatic heterocyclic groupwhich may be substituted, an acyl group having one to six carbon atomswhich may be substituted or an alkylsulfonyl group having one to sixcarbon atoms which may be substituted (provided that a group representedby the formula:

(wherein A represents an aromatic hydrocarbon cyclic group having six tofourteen carbon atoms which may be substituted or a 5 to 14-memberedaromatic heterocyclic group which may be substituted; X¹ and X² are thesame as or different from each other and each represents a carbon atomwhich may be substituted; and X³ represents a nitrogen atom which may besubstituted, an oxygen atom, or a carbon atom which may be substituted)is excluded); R³ represents a cyano group; and R⁴ represents an aromatichydrocarbon cyclic group having six to fourteen carbon atoms which maybe substituted, a 5 to 14-membered aromatic heterocyclic group which maybe substituted or a 5 to 14-membered non-aromatic heterocyclic grouphaving one or more unsaturated bonds which may be substituted; (3) thecompound described in (1), a salt thereof or a solvate of them, whereinR¹ and R² are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted, a 5 to 14-membered aromatic heterocyclic groupwhich may be substituted, an acyl group having one to six carbon atomswhich may be substituted or an alkylsulfonyl group having one to sixcarbon atoms which may be substituted (provided that a group representedby the formula:

(wherein A represents an aromatic hydrocarbon cyclic group having six tofourteen carbon atoms which may be substituted or a 5 to 14-memberedaromatic heterocyclic group which may be substituted; X¹ and X² are thesame as or different from each other and each represents a carbon atomwhich may be substituted; and X³ represents a nitrogen atom which may besubstituted, an oxygen atom or a carbon atom which may be substituted)is excluded); R³ represents a halogen atom, an alkyl group having one tosix carbon atoms which may be substituted, an alkenyl group having twoto six carbon atoms which may be substituted, an alkynyl group havingtwo to six carbon atoms which may be substituted, an aromatichydrocarbon cyclic group having six to fourteen carbon atoms which maybe substituted, a 5 to 14-membered aromatic heterocyclic group which maybe substituted, an oxygen atom which may be substituted or a sulfur atomwhich may be substituted; and R⁴ represents a 4-pyridyl group, a4-pyrimidinyl group, a 4-quinazolinyl group, a 4-quinolyl group or a6-isoquinolinyl, each of which may have one or two substituents; (4) thecompound described in (1), a salt thereof or a solvate of them, whereinR¹ and R² are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted, a 5 to 14-membered aromatic heterocyclic groupwhich may be substituted, an acyl group having one to six carbon atomswhich may be substituted or an alkylsulfonyl group having one to sixcarbon atoms which may be substituted (provided that a group representedby the formula:

(wherein A represents an aromatic hydrocarbon cyclic group having six tofourteen carbon atoms which may be substituted or a 5 to 14-memberedaromatic heterocyclic group which may be substituted; X¹ and X² are thesame as or different from each other and each represents a carbon atomwhich may be substituted; and X³ represents a nitrogen atom which may besubstituted, an oxygen atom or a carbon atom which may be substituted)is excluded); and R⁴ represents a 5 to 14-membered non-aromaticheterocyclic group having at least one or more unsaturated bonds whichmay be substituted (provided that the group represented by the aboveformula (II) is excluded); (5) the compound described in (1), a saltthereof or a solvate of them, wherein R¹ and R² are the same as ordifferent from each other and each represents a hydrogen atom, an alkylgroup having one to six carbon atoms which may be substituted, analkenyl group having two to six carbon atoms which may be substituted,an alkynyl group having two to six carbon atoms which may besubstituted, a cycloalkyl group having three to eight carbon atoms whichmay be substituted, a cycloalkenyl group having three to eight carbonatoms which may be substituted, a 5 to 14-membered non-aromaticheterocyclic group which may be substituted, an aromatic hydrocarboncyclic group having six to fourteen carbon atoms which may besubstituted, a 5 to 14-membered aromatic heterocyclic group which may besubstituted, an acyl group having one to six carbon atoms which may besubstituted or an alkylsulfonyl group having one to six carbon atomswhich may be substituted (provided that a group represented by theformula:

(wherein A represents an aromatic hydrocarbon cyclic group having six tofourteen carbon atoms which may be substituted or a 5 to 14-memberedaromatic heterocyclic group which may be substituted; X¹ and X² are thesame as or different from each other and each represents a carbon atomwhich may be substituted; and X³ represents a nitrogen atom which may besubstituted, an oxygen atom or a carbon atom which may be substituted)is excluded); and R⁴ represents a 4-pyridyl group, a 4-pyrimidinylgroup, a 4-quinazolinyl group, a 4-quinolyl group or a 6-isoquinolinyl,each of which may have one or two substituents including at least one ofa cyano group and a carbamoyl group represented by the formula:

(wherein R⁶ and R⁷ are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted); (6) the compound described in (2), asalt thereof or a solvate of them, wherein R⁴ represents a 5 to14-membered aromatic heterocyclic group which may be substituted or a 5to 14membered non-aromatic heterocyclic group having at least one ormore unsaturated bonds which may be substituted; and R⁵ represents a 5to 14-membered aromatic heterocyclic group which may be substituted; (7)the compound described in (3), a salt thereof or a solvate of them,wherein R³ represents a halogen atom, an alkyl group having one to sixcarbon atoms which may be substituted, an alkenyl group having two tosix carbon atoms which may be substituted, an alkynyl group having twoto six carbon atoms which may be substituted, a 5 to 14-memberedaromatic heterocyclic group which may be substituted, an oxygen atomwhich may be substituted or a sulfur atom which may be substituted; andR⁵ represents a 5 to 14-membered aromatic heterocyclic group which maybe substituted; (8) the compound described in (4), a salt thereof or asolvate of them, wherein R³ represents a hydrogen atom, a halogen atom,a cyano group, an alkyl group having one to six carbon atoms which maybe substituted, an alkenyl group having two to six carbon atoms whichmay be substituted, an alkynyl group having two to six carbon atomswhich may be substituted, a 5 to 14-membered aromatic heterocyclic groupwhich may be substituted, a nitrogen atom which may be substituted, anoxygen atom which may be substituted or a sulfur atom which may besubstituted; and R⁵ represents a 5 to 14-membered aromatic heterocyclicgroup which may be substituted; (9) the compound described in (5), asalt thereof or a solvate of them, wherein R³ represents a hydrogenatom, a halogen atom, a cyano group, an alkyl group having one to sixcarbon atoms which may be substituted, an alkenyl group having two tosix carbon atoms which may be substituted, an alkynyl group having twoto six carbon atoms which may be substituted, a 5 to 14-memberedaromatic heterocyclic group which may be substituted, an oxygen atomwhich may be substituted or a sulfur atom which may be substituted; andR⁵ represents a 5 to 14-membered aromatic heterocyclic group which maybe substituted; (10) the compound described in any one of (1) to (9),wherein R¹ and/or R² represents a hydrogen atom, an alkyl group havingone to six carbon atoms which may be substituted or an acyl group havingone to six carbon atoms which may be substituted (provided that a grouprepresented by the formula:

(wherein A represents an aromatic hydrocarbon cyclic group having six tofourteen carbon atoms which may be substituted or a 5 to 14-memberedaromatic heterocyclic group which may be substituted; X¹ and X² are thesame as or different from each other and each represents a carbon atomwhich may be substituted; and X³ represents a nitrogen atom which may besubstituted, an oxygen atom, or a carbon atom which may be substituted)is excluded), a salt thereof or a solvate of them; (11) the compounddescribed in any one of (1), (4) and (8), wherein R⁴ is a grouprepresented by the formula (IV)

(wherein R⁸ represents a group selected from the following substituentgroup a; and the ring B may be substituted with one to four groupsselected from the following substituent group a.Substituent Group a

The group consisting of a hydrogen atom, a halogen atom, a hydroxylgroup, a nitro group, a cyano group, an alkyl group having one to sixcarbon atoms which may be substituted, an alkenyl group having two tosix carbon atoms which may be substituted, an alkynyl group having twoto six carbon atoms which may be substituted, an alkoxy group having oneto six carbon atoms which may be substituted, an alkenyloxy group havingtwo to six carbon atoms which may be substituted, an alkynyloxy grouphaving two to six carbon atoms which may be substituted, an alkylthiogroup having one to six carbon atoms which may be substituted, analkenylthio group having two to six carbon atoms which may besubstituted, an alkynylthio group having two to six carbon atoms whichmay be substituted, an aliphatic acyl group having two to seven carbonatoms, a carbamoyl group which may be substituted, an arylacyl group, aheteroarylacyl group, an amino group which may be substituted, analkylsulfonyl group having one to six carbon atoms which may besubstituted, an alkenylsulfonyl group having two to six carbon atomswhich may be substituted, an alkynylsulfonyl group having two to sixcarbon atoms which may be substituted, an alkylsulfinyl group having oneto six carbon atoms which may be substituted, an alkenylsulfinyl grouphaving two to six carbon atoms which may be substituted, analkynylsulfinyl group having two to six carbon atoms which may besubstituted, a formyl group, a cycloalkyl group having three to eightcarbon atoms which may be substituted, a cycloalkenyl group having threeto eight carbon atoms which may be substituted, a 5 to 14-memberednon-aromatic heterocyclic group which may be substituted, an aromatichydrocarbon cyclic group having six to fourteen carbon atoms which maybe substituted and a 5 to 14-membered aromatic heterocyclic group whichmay be substituted), a salt thereof or a solvate of them; (12) thecompound described in (11), a salt thereof or a solvate of them, whereinR³ is a hydrogen atom, a halogen atom, a cyano group, an alkyl grouphaving one to six carbon atoms which may be substituted, a 5 to14-membered aromatic heterocyclic group which may be substituted, anamino group or an oxygen atom which may be substituted; (13) thecompound described in (11) or (12), wherein R⁴ is a group represented bythe formula:

or the formula:

(in the formulae (V) and (VI), R⁸ represents a group selected from thefollowing substituent group a; and the ring B may be substituted withone to four groups selected from the following substituent group a.Substituent Group a

The group consisting of a hydrogen atom, a halogen atom, a hydroxylgroup, a nitro group, a cyano group, an alkyl group having one to sixcarbon atoms which may be substituted, an alkenyl group having two tosix carbon atoms which may be substituted, an alkynyl group having twoto six carbon atoms which may be substituted, an alkoxy group having oneto six carbon atoms which may be substituted, an alkenyloxy group havingtwo to six carbon atoms which may be substituted, an alkynyloxy grouphaving two to six carbon atoms which may be substituted, an alkylthiogroup having one to six carbon atoms which may be substituted, analkenylthio group having two to six carbon atoms which may besubstituted, an alkynylthio group having two to six carbon atoms whichmay be substituted, an aliphatic acyl group having two to seven carbonatoms, a carbamoyl group which may be substituted, an arylacyl group, aheteroarylacyl group, an amino group which may be substituted, analkylsulfonyl group having one to six carbon atoms which may besubstituted, an alkenylsulfonyl group having two to six carbon atomswhich may be substituted, an alkynylsulfonyl group having two to sixcarbon atoms which may be substituted, an alkylsulfinyl group having oneto six carbon atoms which may be substituted, an alkenylsulfinyl grouphaving two to six carbon atoms which may be substituted, analkynylsulfinyl group having two to six carbon atoms which may besubstituted, a formyl group, a cycloalkyl group having three to eightcarbon atoms which may be substituted, a cycloalkenyl group having threeto eight carbon atoms which may be substituted, a 5 to 14-memberednon-aromatic heterocyclic group which may be substituted, an aromatichydrocarbon cyclic group having six to fourteen carbon atoms and a 5 to14-membered aromatic heterocyclic group which may be substituted), asalt thereof or a solvate of them; (14) the compound described in anyone of (1), (3) and (7), a salt thereof or a solvate of them, wherein R⁴is 4-pyridyl group which may have one or two substituents; (15) thecompound described in (14), a salt thereof or a solvate of them, whereinR³ is a halogen atom, a cyano group, an alkyl group having one to sixcarbon atoms which may be substituted, a 5 to 14-membered aromaticheterocyclic group which may be substituted or an oxygen atom which maybe substituted; (16) the compound described in (14) or (15), wherein R⁴is a 4-pyridyl group which may have one or two substituents comprisingat least one of a cyano group and a carbamoyl group represented by theformula (III):

(wherein R⁶ and R⁷ are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted), a salt thereof or a solvate of them;(17) the compound described in any one of (1) to (5), a salt thereof ora solvate of them, wherein R⁵ is a naphthyl group or a phenyl group,each of which may be substituted; (18) the compound described in any oneof (1) to (16), a salt thereof or a solvate of them, wherein R⁵ ispyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group,pyrazinyl group, thienyl group, thiazolyl group, furyl group, quinolinylgroup, isoquinolinyl group, phthalazinyl group, naphthyridinyl group,indolyl group or isoindolyl group, each of which may be substituted;(19) a pharmaceutical composition comprising the compound described inany one of (1) to (18), a salt thereof or a solvate of them; (20) thecomposition described in (19), which is an agent for treating orpreventing a disease to which an adenosine receptor relates; (21) thecomposition described in (19), which is an agent for treating orpreventing a disease to which an adenosine A₂ receptor relates; (22) thecomposition described in (19), which is an agent for treating orpreventing a disease to which an adenosine A_(2A) receptor relates; (23)the composition described in (19), which is an agent for treating orpreventing a disease to which an adenosine A_(2B) receptor relates; (24)the composition described in (19), which is an adenosine receptorantagonist; (25) the composition described in (19), which is anadenosine A₂ receptor antagonist; (26) the composition described in(19), which is adenosine A_(2A) receptor antagonist; (27) thecomposition described in (19), which is adenosine A_(2B) receptorantagonist; (28) the composition described in any one of (19) to (22),(24) to (26), which is an agent for treating Parkinson's disease or anantidepressant; (29) the composition described in any one of (19) to(21), (23) to (25) and (27), which is a defecation-promoting agent; (30)the composition described in any one of (19) to (21), (23) to (25) and(27), which is an agent for treating, preventing or improvingconstipation; (31) the composition described in (30), wherein theconstipation is functional constipation; (32) the composition describedin (30), which is an agent for treating, preventing or improvingirritable bowel syndrome, constipation accompanying irritable bowelsyndrome, organic constipation, constipation accompanyingenteroparalytic ileus, constipation accompanying congenital digestivetract dysfunction or constipation accompanying ileus; (33) thecomposition described in (19), which is used for evacuating intestinaltracts at the time of examination of digestive tracts or be fore andafter an operation; (34) use of the compound described in any one of (1)to (18), a salt thereof or a solvate of them for producing adefecation-promoting agent; (35) the composition described in (19),which is an agent for treating or preventing diabetes mellitus, diabeticcomplications, diabetic retinopathy, obesity or asthma; (36) thecomposition described in (19), which is a hypoglycemic agent, an agentfor improving glucose intolerance or an insulin sensitizer; and (37) thecomposition described in (19), which is a hypotensive agent, a diureticagent, an agent for treating osteoporosis, an agent for treatingAlzheimer's disease, an agent for treating an inflammatory bowel diseaseor an agent for treating Crohn's disease.

Hereinafter, the meanings of symbols, terms, etc. used in the presentdescription will be described, and the present invention will beillustrated in detail.

In the present description, the “antagonist” refers to an agent whichhas affinity for and inactivates an adenosine receptor, preferably anadenosine A₂ receptor, that is, an A_(2A) and/or A_(2B) receptor.

The “disease to which an adenosine receptor relates” used in the presentdescription refers to a disease to which an adenosine A₁ receptor,A_(2A) receptor, A_(2B) receptor or A₃ receptor relates, and includesvarious constipation (e.g., functional constipation, irritable bowelsyndrome, constipation accompanying irritable bowel syndrome, organicconstipation, constipation accompanying enteroparalytic ileus,constipation accompanying congenital digestive tract dysfunction andconstipation accompanying ileus), diabetes mellitus, diabeticcomplications, diabetic retinopathy, obesity, asthma, as well asdiseases against which a hypoglycemic agent, agent for improving glucoseintolerance, insulin sensitizer, antihypertensive drug, diuretic agent,antidepressant, agent for treating osteoporosis, agent for treatingParkinson's disease, agent for treating Alzheimer's disease, agent fortreating an inflammatory bowel disease or agent for treating Crohn'sdisease is efficacious.

The present invention provides a method for treating or preventing adisease to which an adenosine receptor relates, and a method forpromoting defecation, which comprises administering a pharmacologicallyeffective dose of the compound represented by the formula (I), a saltthereof or a solvate of them to a patient.

The present invention further provides use of the compound representedby the formula (I), a salt thereof or a solvate of them for producing anagent for treating or preventing a disease to which an adenosinereceptor relates, or a defecation-promoting agent.

The compound represented by the formula (I), a salt thereof or a solvateof them is also useful as a defecation-promoting agent and is used forevacuating intestinal tracts at the time of examination of digestivetracts or be fore and after an operation.

The term “and/or” used in the present description means and includesboth the cases of “and” and “or”.

In the present description, there is the case where the structuralformula of a compound represents a definite isomer for the sake ofconvenience. However, the present invention includes all isomers such asgeometrical isomers, optical isomers based on asymmetric carbon,rotational isomer, stereoisomers and tautomers, and mixtures of theseisomers and is not limited by the description of the formula illustratedfor the sake of convenience. The compound can be any of isomers or amixture thereof. Accordingly, although it is possible that an asymmetriccarbon atom is present in a molecule and that optically active substanceand racemic substance may therefore be present, the present invention isnot limited thereto but covers any of them. Further, crystalpolymorphism may be present but, again, there is no limitation but anyof single crystal form or a mixture will do. The compound (I) or itssalt according to the present invention may be a non-solvate or asolvate, and either of them are included in the scope of claims forpatent in the present invention. A metabolite which is generated bydecomposing the compound (I) according to the present invention in vivo,and a prodrug of the compound (I) or its salt according to the presentinvention are also included in the scope of claims for patent in thepresent invention.

The “halogen atom” used in the present description represents an atomsuch as fluorine atom, chlorine atom, bromine atom or iodine atom, andfluorine atom, chlorine atom and bromine atom are preferred.

The “C₁₋₆ alkyl group” used in the present description represents analkyl group having one to six carbon atoms, including linear or branchedalkyl groups such as methyl group, ethyl group, n-propyl group,iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group,t-butyl group, n-pentyl group, 1,1-dimethylpropyl group,1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group,2-ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl group,1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group,1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group,1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutylgroup, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutylgroup, 2-methylpentyl group or 3-methylpentyl group.

The “C₂₋₆ alkenyl group” used in the present description represents analkenyl group having two to six carbon atoms, and suitable examples ofthe group are vinyl group, allyl group, 1-propenyl group, 2-propenylgroup, isopropenyl group, 2-methyl-1-propenyl group, 3-methyl-1-propenylgroup, 2-methyl-2-propenyl group, 3-methyl-2-propenyl group, 1-butenylgroup, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 1-hexenylgroup, 1,3-hexadienyl group and 1,6-hexadienyl group.

The “C₂₋₆ alkynyl group” used in the present description represents analkynyl group having two to six carbon atoms, and suitable examples ofthe group are ethynyl group, 1-propynyl group, 2-propynyl group,1-butynyl group, 2-butynyl group, 3-butynyl group, 3-methyl-1-propynylgroup, 1-ethynyl-2-propynyl group, 2-methyl-3-propynyl group, 1-pentynylgroup, 1-hexynyl group, 1,3-hexadiynyl group, and 1,6-hexadiynyl group.

The “C₁₋₆ alkoxy group” used in the present description represents analkoxy group having one to six carbon atoms, such as methoxy group,ethoxy group, n-propoxy group, iso-propoxy group, sec-propoxy group,n-butoxy group, iso-butoxy group, sec-butoxy group, t-butoxy group,n-pentyloxy group, iso-pentyloxy group, sec-pentyloxy group, n-hexoxygroup, iso-hexoxy group, 1,1-dimethylpropyloxy group,1,2-dimethylpropoxy group, 2,2-dimethylpropyloxy group, 2-ethylpropoxygroup, 1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group,1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxy group,1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutyloxygroup, 2-ethylbutoxy group, 1,3-dimethylbutoxy group, 2-methylpentoxygroup, 3-methylpentoxy group or hexyloxy group.

The “C₂₋₆ alkenyloxy group” used in the present description representsan alkenyloxy group having two to six carbon atoms, and suitableexamples of the group are vinyloxy group, allyloxy group, 1-propenyloxygroup, 2-propenyloxy group, isopropenyloxy group, 2-methyl-1-propenyloxygroup, 3-methyl-1-propenyloxy group, 2-methyl-2-propenyloxy group,3-methyl-2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group,3-butenyloxy group, 1-pentenyloxy group, 1-hexenyloxy group,1,3-hexadienyloxy group, and 1,6-hexadienyloxy group.

The “C₂₋₆ alkynyloxy group” used in the present description representsan alkynyloxy group having two to six carbon atoms, and suitableexamples thereof are ethynyloxy group, 1-propynyloxy group,2-propynyloxy group, 1-butynyloxy group, 2-butynyloxy group,3-butynyloxy group, 3-methyl-1-propynyloxy group,1-ethynyl-2-propynyloxy group, 2-methyl-3-propynyloxy group,1-pentynyloxy group, 1-hexynyloxy group, 1,3-hexadiynyloxy group, and1,6-hexadiynyloxy group.

The “alkylthio group having one to six carbon atoms” used in the presentdescription refers to an alkylthio group having one to six carbon atoms,such as methylthio group, ethylthio group, n-propylthio group,iso-propylthio group, sec-propylthio group, n-butylthio group,iso-butylthio group, sec-butylthio group, t-butylthio group,n-pentylthio group, iso-pentylthio group, sec-pentylthio group,n-hexylthio group, iso-hexylthio group, 1,1-dimethylpropylthio group,1,2-dimethylpropylthio group, 2,2-dimethylpropylthio group,2-ethylpropylthio group, 1-methyl-2-ethylpropylthio group,1-ethyl-2-methylpropylthio group, 1,1,2-trimethylpropylthio group,1,1-dimethylbutylthio group, 1,2-dimethylbutylthio group,2,2-dimethylbutylthio group,2,3-dimethylbutylthio group,1,3-dimethylbutylthio group, 2-ethylbutylthio group, 2-methylpentylthiogroup or 3-methylpentylthio group.

The “alkenylthio group having two to six carbon atoms” used in thepresent description refers to an alkenylthio group having two to sixcarbon atoms, and suitable examples thereof are vinylthio group,allylthio group, 1-propenylthio group, 2-propenylthio group,isopropenylthio group, 2-methyl-1-propenylthio group,3-methyl-1-propenylthio group, 2-methyl-2-propenylthio group,3-methyl-2-propenylthio group, 1-butenylthio group, 2-butenylthio group,3-butenylthio group, 1-pentenylthio group, 1-hexenylthio group,1,3-hexadienylthio group, and 1,6-hexadienylthio group.

The “alkynylthio group having two to six carbon atoms” used in thepresent description represents an alkynylthio group having two to sixcarbon atoms, and suitable examples thereof are ethynylthio group,1-propynylthio group, 2-propynylthio group, 1-butynylthio group,2-butynylthio group, 3-butynylthio group, 3-methyl-1-propynylthio group,1-ethynyl-2-propynylthio group, 2-methyl-3-propynylthio group,1-pentynylthio group, 1-hexynylthio group, 1,3-hexadiynylthio group, and1,6-hexadiynylthio group.

The “cycloalkyl group having three to eight carbon atoms” used in thepresent description represents a cycloalkyl group comprising three toeight carbon atoms, such as cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group, cycloheptyl group or cyclooctylgroup.

The “cycloalkenyl group having three to eight carbon atoms” used in thepresent invention represents a cycloalkenyl group comprising three toeight carbon atoms, such as cyclopropen-1-yl, cyclopropen-3-yl,cyclobuten-1-yl, cyclobuten-3-yl, 1,3-cyclobutadien-1-yl,cyclopenten-1-yl, cyclopenten-3-yl, cyclopenten-4-yl,1,3-cyclopentadien-1-yl, 1,3-cyclopentadien-2-yl,1,3-cyclopentadien-5-yl, cyclohexen-1-yl, cyclohexen-3-yl,cyclohexen-4-yl, 1,3-cyclohexadien-1-yl, 1,3-cyclohexadien-2-yl,1,3-cyclohexadien-5-yl, 1,4-cyclohexadien-3-yl, 1,4-cyclohexadien-1-yl,cyclohepten-1-yl, cyclohepten-3-yl, cyclohepten-4-yl, cyclohepten-5-yl,1,3-cyclohepten-2-yl, 1,3-cyclohepten-1-yl, 1,3-cycloheptadien-5-yl,1,3-cycloheptadien-6-yl, 1,4-cycloheptadien-3-yl,1,4-cycloheptadien-2-yl, 1,4-cycloheptadien-1-yl,1,4-cycloheptadien-6-yl, 1,3,5-cycloheptatrien-3-yl,1,3,5-cycloheptatrien-2-yl, 1,3,5-cycloheptatrien-1-yl,1,3,5-cycloheptatrien-7-yl, cycloocten-1-yl, cycloocten-3-yl,cycloocten-4-yl, cycloocten-5-yl, 1,3-cyclooctadien-2-yl,1,3-cyclooctadien-1-yl, 1,3-cyclooctadien-5-yl, 1,3-cyclooctadien-6-yl,1,4-cyclooctadien-3-yl, 1,4-cyclooctadien-2-yl, 1,4-cyclooctadien-1-yl,1,4-cyclooctadien-6-yl, 1,4-cyclooctadien-7-yl, 1,5-cyclooctadien-3-yl,1,5-cyclooctadien-2-yl, 1,3,5-cyclooctatrien-3-yl,1,3,5-cyclooctatrien-2-yl, 1,3,5-cyclooctatrien-1-yl,1,3,5-cyclooctatrien-7-yl, 1,3,6-cyclooctatrien-2-yl,1,3,6-cyclooctatrien-1-yl, 1,3,6-cyclooctatrien-5-yl or1,3,6-cyclooctatrien-6-yl group.

The “5 to 14-membered non-aromatic heterocyclic group” used in thepresent description refers to a monocyclic, bicyclic or tricyclic 5 to14-membered non-aromatic heterocyclic group and containing one or morehetero atoms selected from the group consisting of nitrogen atom, sulfuratom and oxygen atom. Specific examples of the group are pyrrolidinylgroup, piperidinyl group, piperazinyl group, pyrazolinyl group,morpholinyl group, tetrahydrofuryl group, tetrahydropyranyl group,dihydrofuryl group, dihydropyranyl group, imidazolinyl group, andoxazolinyl group. The non-aromatic heterocyclic group also includes agroup derived from pyridone ring, and a non-aromatic fused ring (e.g., agroup derived from phthalimide ring or succinimide ring).

The “aromatic cyclic hydrocarbon group having six to fourteen carbonatoms” and the “aryl” used in the present description represent anaromatic cyclic hydrocarbon group comprising six to fourteen carbonatoms and include monocyclic groups, as well as fused groups such asbicyclic groups and tricyclic groups. Specific examples of the groupinclude phenyl group, indenyl group, 1-naphthyl group, 2-naphthyl group,azulenyl group, heptalenyl group, biphenyl group, indacenyl group,acenaphthyl group, fluorenyl group, phenalenyl group, phenanthrenylgroup, anthracenyl group, cyclopentacyclooctenyl group, andbenzocyclooctenyl group.

The “5 to 14-membered aromatic heterocyclic group” and the “heteroaryl”used in the present description represent a monocyclic, bicyclic ortricyclic 5 to 14-membered aromatic heterocyclic group containing one ormore hetero atoms selected from nitrogen atom, sulfur atom and oxygenatom. Specific examples of the group include 1) a nitrogen-containingaromatic heterocyclic group such as pyrrolyl group, pyridyl group,pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group,tetrazolyl group, benzotriazolyl group, pyrazolyl group, imidazolylgroup, benzimidazolyl group, indolyl group, isoindolyl group,indolizinyl group, purinyl group, indazolyl group, quinolyl group,isoquinolyl group, quinolizyl group, phthalazyl group, naphthyridinylgroup, quinoxalyl group, quinazolinyl group, cinnolinyl group,pteridinyl group, imidazotriazinyl group, pyrazinopyridazinyl group,acridinyl group, phenanthridinyl group, carbazolyl group, carbazolinylgroup, perimidinyl group, phenanthrolinyl group, phenacinyl group,imidazopyridinyl group, imidazopyrimidinyl group, pyrazolopyridinylgroup or pyrazolopyridinyl group; 2) a sulfur-containing aromaticheterocyclic group such as thienyl group or benzothienyl group; 3) anoxygen-containing aromatic heterocyclic group such as furyl group,pyranyl group, cyclopentapyranyl group, benzofuryl group orisobenzofuryl group; and 4) an aromatic heterocyclic group containingtwo or more different hetero atoms, such as thiazolyl group,isothiazolyl group, benzothiazolyl group, benzthiadiazolyl group,phenothiazinyl group, isoxazolyl group, furazanyl group, phenoxazinylgroup, oxazolyl group, isoxazoyl group, benzoxazolyl group, oxadiazolylgroup, pyrazolooxazolyl group, imidazothiazolyl group, thienofuranylgroup, furopyrrolyl group or pyridooxazinyl group.

The “aliphatic acyl group having two to seven carbon atoms” used in thepresent description represents an atomic group derived from an aliphaticcarboxyl group having two to seven carbon atoms by removing OH groupfrom its carboxyl group, and suitable examples thereof are acetyl group,propionyl group and butyroyl group.

The “arylacyl group” used in the present description represents acarbonyl group substituted with an aromatic cyclic hydrocarbon grouphaving six to fourteen carbon atoms, and the “heteroarylacyl group”represents a carbonyl group substituted with a 5 to 14-membered aromaticheterocyclic group. The “aromatic cyclic hydrocarbon group having six tofourteen carbon atoms” and the “5 to 14-membered aromatic heterocyclicgroup” as used herein have the same meanings as defined above.

Suitable examples of the “alkylsulfonyl group having one to six carbonatoms”, “alkenylsulfonyl group having two to six carbon atoms” and“alkynylsulfonyl group having two to six carbon atoms” used in thepresent description include methylsulfonyl group, ethylsulfonyl group,n-propylsulfonyl group, iso-propylsulfonyl group, n-butylsulfonyl group,t-butylsulfonyl group, vinylsulfonyl group, allylsulfonyl group,iso-propenylsulfonyl group, iso-pentenylsulfonyl group, andethynylsulfonyl group. Suitable examples of the “alkylsulfinyl grouphaving one to six carbon atoms”, “alkenylsulfinyl group having two tosix carbon atoms” and “alkynylsulfinyl group having two to six carbonatoms” used in the present description include methylsulfinyl group,ethylsulfinyl group, n-propylsulfinyl group, iso-propylsulfinyl group,n-butylsulfinyl group, t-butylsulfinyl group, vinylsulfinyl group,allylsulfinyl group, iso-propenylsulfinyl group, iso-pentenylsulfinylgroup, and ethynylsulfinyl group.

Examples of the “substituents” in the “amino group which may besubstituted” used in the present description represents one or twogroups selected from an alkyl group having one to six carbon atoms, analkenyl group having two to six carbon atoms, an alkynyl group havingtwo to six carbon atoms, an alkylsulfonyl group having one to six carbonatoms, an alkenylsulfonyl group having two to six carbon atoms,alkynylsulfonyl group having two to six carbon atoms, an alkylcarbonylgroup having one to six carbon atoms, an alkenylcarbonyl group havingtwo to six carbon atoms, an alkynylcarbonyl group having two to sixcarbon atoms, each of which may be substituted. In this connection, thesubstituents may be combined to form a 3 to 8-memberednitrogen-containing ring. Suitable examples of the “substituents” in thealkyl group having one to six carbon atoms, alkenyl group having two tosix carbon atoms, alkynyl group having two to six carbon atoms,alkylsulfonyl group having one to six carbon atoms, alkenylsulfonylgroup having two to six carbon atoms, alkynylsulfonyl group having twoto six carbon atoms, C₁₋₆ alkylcarbonyl group, C₂₋₆ alkenylcarbonylgroup and C₂₋₆ alkynylcarbonyl group include a hydroxyl group, a halogenatom, a nitrile group, an alkoxy group and C₁₋₆ alkylthio group.Particularly preferable examples of the above-mentioned “amino groupwhich may be substituted” include methylamino group, ethylamino group,n-propylamino group, iso-propylamino group, n-butylamino group,iso-butylamino group, tert-butylamino group, n-pentylamino group,iso-pentylamino group, neopentylamino group, n-hexylamino group,1-methylpropylamino group, 1,2-dimethylpropylamino group,2-ethylpropylamino group, 1-methyl-2-ethylpropylamino group,1-ethyl-2-methylpropylamino group, 1,1,2-trimethylpropylamino group,1-methylbutylamino group, 2-methylbutylamino group,1,1-dimethylbutylamino group, 2,2-dimethylbutylamino group,2-ethylbutylamino group, 1,3-dimethylbutylamino group,2-methylpentylamino group, 3-methylpentylamino group, N,N-dimethylaminogroup, N,N-diethylamino group, N,N-di(n-propyl)amino group,N,N-di(iso-propyl)amino group, N,N-di(n-butyl)amino group,N,N-di(iso-butyl)amino group, N,N-di(t-butyl)amino group,N,N-di(n-pentyl)amino group, N,N-di (iso-pentyl)amino group,N,N-di(neopentyl)amino group, N,N-di (n-hexyl)amino group,N,N-di(1-methylpropyl)amino group, N,N-di(1,2-dimethylpropyl)aminogroup, N-methyl-N-ethylamino group, N-ethyl-N-(n-propyl)amino group,N-methyl-N-(i-propyl)amino group, vinylamino group, allylamino group,(1-propenyl)amino group, isopropenylamino group, (1-buten-1-yl)aminogroup, (1-buten-2-yl)amino group, (1-buten-3-yl)amino group,(2-buten-1-yl)amino group, (2-buten-2-yl)amino group, N,N-divinylaminogroup, N,N-diallylamino group, N,N-di(1-propenyl)amino group,N,N-isopropenylamino group, N-vinyl-N-allylamino group, ethynylaminogroup, 1-propynylamino group, 2-propynylamino group, butynylamino group,pentynylamino group, hexynylamino group, N,N-diethynylamino group,N,N-(1-propynyl)amino group, N,N-(2-propynyl)amino group,N,N-dibutynylamino group, N,N-dipentynylamino group, N,N-dihexynylaminogroup, hydroxymethylamino group, 1-hydroxyethylamino group,2-hydroxyethylamino group, 3-hydroxy-n-propyl group, methylsulfonylaminogroup, ethylsulfonylamino group, n-propylsulfonylamino group,iso-propylsulfonylamino group, n-butylsulfonylamino group,t-butylsulfonylamino group, vinylsulfonylamino group, allylsulfonylaminogroup, iso-propenylsulfonylamino group, iso-pentenylsulfonylamino group,ethynylsulfonylamino group, methylcarbonylamino group,ethylcarbonylamino group, n-propylcarbonylamino group,iso-propylcarbonylamino group, n-butylcarbonylamino group,butylcarbonylamino group, vinylcarbonylamino group, allylcarbonylaminogroup, iso-propenylcarbonylamino group, iso-pentenylcarbonylamino group,and ethynylcarbonylamino group.

Examples of the “substituents” in the phrase “which may be substituted”used in the present description include a halogen atom such as fluorineatom, chlorine atom, bromine atom or iodine atom; a hydroxyl group; anitro group; a cyano group; an alkyl group having one to six carbonatoms such as methyl group, ethyl group, n-propyl group, iso-propylgroup, n-butyl group, iso-butyl group, sec-butyl group, t-butyl group,n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group,2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group,n-hexyl group or 1-methyl-2-ethylpropyl group; an alkenyl group havingtwo to six carbon atoms such as vinyl group, allyl group, 1-propenylgroup, 2-propenyl group, isopropenyl group, 2-methyl-1-propenyl group,3-methyl-1-propenyl group, 2-methyl-2-propenyl group,3-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenylgroup, 1-pentenyl group, 1-hexenyl group, 1,3-hexadienyl group or1,6-hexadienyl group; an alkynyl group having two to six carbon atomssuch as ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynylgroup, 2-butynyl group, 3-butynyl group, 3-methyl-1-propynyl group,1-ethyny1-2-propynyl group, 2-methyl-3-propynyl group, 1-pentynyl group,1-hexynyl group, 1,3-hexadiynyl group or 1,6-hexadiynyl group; an alkoxygroup having one to six carbon atoms such as methoxy group, ethoxygroup, n-propoxy group, iso-propoxy group, sec-propoxy group, n-butoxygroup, iso-butoxy group, sec-butoxy group, t-butoxy group, n-pentyloxygroup, iso-pentyloxy group, sec-pentyloxy group or n-hexyloxy group; analkenyloxy group having two to six carbon atoms such as vinyloxy group,allyloxy group, 1-propenyloxy group, 2-propenyloxy group orisopropenyloxy group; an alkynyloxy group having two to six carbon atomssuch as ethynyloxy group, 1-propynyloxy group or 2-propynyloxy group; analkylthio group having one to six carbon atoms such as methylthio group,ethylthio group, n-propylthio group, iso-propylthio group,sec-propyithic group, n-butylthio group, iso-butylthio group,sec-butylthio group or t-butylthio group; an alkenylthio group havingtwo to six carbon atoms such as vinylthio group, allylthio group,1-propenylthio group or 2-propenylthio group; an alkynylthio grouphaving two to six carbon atoms such as ethynylthio group, 1-propynylthiogroup or 2-propynylthio group; an aliphatic acyl group having two toseven carbon atoms such as acetyl group, propionyl group or butyroylgroup; carbamoyl group; an arylacyl group; a heteroarylacyl group; anamino group; an alkylsulfonyl group having one to six carbon atoms, analkenylsulfonyl group having two to six carbon atoms, an alkynylsulfonylgroup having two to six carbon atoms, an alkylsulfinyl group having oneto six carbon atoms, an alkenylsulfinyl group having two to six carbonatoms or an alkynylsulfinyl group having two to six carbon atoms, suchas methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group,iso-propylsulfonyl group, n-butylsulfonyl group, t-butylsulfonyl group,vinylsulfonyl group, allylsulfonyl group, iso-propenylsulfonyl group,iso-pentenylsulfonyl group, ethynylsulfonyl group, methylsulfinyl group,ethylsulfinyl group, n-propylsulfinyl group, iso-propylsulfinyl group,n-butylsulfinyl group, t-butylsulfinyl group, vinylsulfinyl group,allylsulfinyl group, iso-propenylsulfinyl group, iso-pentenylsulfinylgroup or ethynylsulfinyl group; a formyl group, a cycloalkyl grouphaving three to eight carbon atoms such as cyclopropyl group, cyclobutylgroup, cyclopentyl group, cyclohexyl group, cycloheptyl group orcyclooctyl group; a cycloalkenyl group having three to eight carbonatoms such as cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenylgroup; a 5to 14-membered non-aromatic heterocyclic group, such aspyrrolidinyl group, pyrrolyl group, piperidinyl group, piperazinylgroup, imidazolyl group, pyrazolidyl group, imidazolidyl group,morpholinyl group, tetrahydrofuryl group, tetrahydropyranyl group,pyrrolinyl group, dihydrofuryl group, dihydropyranyl group, imidazolinylgroup, oxazolinyl group, a group derived from pyridone ring, and a groupderived from phthalimide ring or succinimide ring; an aromatic cyclichydrocarbon group having six to fourteen carbon atoms such as phenylgroup, indenyl group, 1-naphthyl group, 2-naphthyl group, biphenyl groupor indacenyl group; a 5 to 14-membered aromatic heterocyclic group, suchas pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group,pyrazinyl group, triazolyl group, tetrazolyl group, benzotriazolylgroup, pyrazolyl group, imidazolyl group, benzimidazolyl group, indolylgroup, isoindolyl group, indolizinyl group, purinyl group, indazolylgroup, quinolyl group, isoquinolyl group, quinolizinyl group,phthalazinyl group, naphthyridinyl group, quinoxalyl group, quinazolinylgroup, cinnolinyl group, pteridinyl group, imidazotriazinyl group,pyrazinopyridazinyl group, acridinyl group, phenanthridinyl group,carbazolyl group, carbazolinyl group, perimidinyl group, phenanthrolinylgroup, phenacynyl group, imidazopyridyl group, imidazopyrimidinyl group,pyrazolopyridyl group, pyrazolopyridyl group, thienyl group,benzothienyl group, furyl group, pyranyl group, cyclopentapyranyl group,benzofuryl group, isobenzofuryl group, thiazolyl group, isothiazolylgroup, benzothiazolyl group, benzothiadiazolyl group, phenothiazinylgroup, isoxazolyl group, furazanyl group, phenoxazinyl group, oxazolylgroup, isoxazolyl group, benzoxazolyl group, oxadiazolyl group,pyrazolooxazolyl group, imidazothiazolyl group, thienofuranyl group,furopyrrolyl group or pyridooxazinyl group. Each of these substituentsmay be further substituted.

In the formula (I), suitable examples of the “substituents” in the“carbamoyl group which may be substituted” are groups selected from analkyl group having one to six carbon atoms which may be substituted, analkenyl group having two to six carbon atoms which may be substituted,an alkynyl group having two to six carbon atoms which may besubstituted, a cycloalkyl group having three to eight carbon atoms whichmay be substituted, a cycloalkenyl group having three to eight carbonatoms which may be substituted, an aromatic cyclic hydrocarbon grouphaving six to fourteen carbon atoms which may be substituted, and a 5 to14-membered aromatic heterocyclic group which may be substituted. Thenitrogen atom of the carbamoyl group may be substituted with one or twogroups selected from the above group of substituents. The substituentsmay be combined to form a 3 to 14-membered nitrogen-containing ring,such as pyrrolidyl group, pyrrolinyl group, piperidyl group, piperazinylgroup, imidazolyl group, pyrazolidyl group, imidazolidyl group,morpholinyl group, tetrahydropyranyl group, aziridinyl group, oxiranylgroup, oxathiolanyl group, phthalimidyl group, succinimidyl group,pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group,pyrazinyl group or pyrazolyl group. In addition, the nitrogen-containingring may be substituted.

In the formula (I), a preferred group in R¹ and/or R² is notspecifically limited, of which a hydrogen atom, an alkyl group havingone to six carbon atoms and an aliphatic acyl group having two to sevencarbon atoms, each of which may be substituted, are more preferred, anda hydrogen atom is typically preferred.

In the formula (I), a preferred group in R³ is not specifically limited,of which a hydrogen atom, an amino group, a cyano group, and an alkylgroup having one to six carbon atoms, an alkoxy group having one to sixcarbon atoms, a phenyl group, a naphthyl group, a pyridyl group, apyridazyl group, a pyrimidyl group, a pyrazyl group, a thienyl group, afuryl group, an imidazolyl group etc., each of which may be substitutedare more preferred, and a hydrogen atom is further preferred.

In the formula (I), R⁴ represents an aromatic cyclic hydrocarbon grouphaving six to fourteen carbon atoms which may be substituted, a 5 to14-membered non-aromatic heterocyclic group having one or moreunsaturated bonds or a 5 to 14-membered aromatic heterocyclic groupwhich may be substituted, and suitable examples thereof are an aromaticcyclic hydrocarbon group having six to fourteen carbon atoms such asphenyl group or naphthyl group; a 5 to 14-membered non-aromaticheterocyclic group, such as pyrrolidinyl group, pyrrolinyl group,piperidinyl group, piperazinyl group, imidazolinyl group, pyrazolidinylgroup, imidazolidinyl group, morpholinyl group, tetrahydropyranyl group,aziridinyl group, oxiranyl group, oxathiolanyl group,6-oxo-1,6-dihydropyridinyl group in which the nitrogen atom may besubstituted or 2-oxo-1,2-dihydropyridinyl group in which the nitrogenatom may be substituted; ora 5 to 14-membered aromatic heterocyclicgroup, such as pyrrolyl group, pyridyl group, pyridazinyl group,pyrimidinyl group, pyrazinyl group, pyrazolyl group, imidazolyl group,indolyl group, isoindolyl group, indolizinyl group, quinolyl group,isoquinolyl group, quinolizinyl group, phthalazinyl group, naphthyridylgroup, quinoxalyl group, quinazolyl group, imidazotriazinyl group,pyrazinopyridazinyl group, thienyl group, benzothienyl group, furylgroup, pyranyl group, cyclopentapyranyl group, benzofuryl group,isobenzofuryl group, thiazolyl group, isothiazolyl group, benzothiazolylgroup, benzothiadiazolyl group, phenothiazyl group, isoxazolyl group,pyrazolooxazolyl group, imidazothiazolyl group, thienofuryl group,furopyrrolyl group or pyridooxazinyl group. Each of these groups may befurther substituted. More preferred examples of R⁴ include groupsrepresented by the formulae:

each of which may be substituted. When the 6-oxo-1,6-dihydropyridylgroup or 2-oxo-1,2-dihydropyridyl group has a substituent, thesubstituent may also be combined with the nitrogen atom.

In the formula (I), R⁵ refers to an aromatic cyclic hydrocarbon grouphaving six to fourteen carbon atoms or a 5 to 14-membered aromaticheterocyclic group, each of which may be substituted, and suitableexamples there of include an aromatic cyclic hydrocarbon group havingsix to fourteen carbon atoms such as phenyl group or naphthyl group, ora 5 to 14-membered aromatic heterocyclic group, such as pyrrolyl group,pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group,pyrazolyl group, imidazolyl group, indolyl group, isoindolyl group,indolizinyl group, quinolyl group, isoquinolyl group, quinolizinylgroup, phthalazinyl group, naphthyridyl group, quinoxalyl group,quinazolyl group, imidazotriazinyl group, pyrazinopyridazinyl group,thienyl group, benzothienyl group, furyl group, pyranyl group,cyclopentapyranyl group, benzofuryl group, isobenzofuryl group,thiazolyl group, isothiazolyl group, benzothiazolyl group,benzothiadiazolyl group, phenothiazyl group, isoxazolyl group,pyrazolooxazolyl group, imidazothiazolyl group, thienofuryl group,furopyrrolyl group or pyridooxazinyl group. Each of these groups may besubstituted. More preferred examples of R⁵ include groups represented bythe formulae:

each of which may be substituted.

In the “substituents” in the “aromatic cyclic hydrocarbon group havingsix to fourteen carbon atoms which may be substituted” and the “5 to14-membered aromatic heterocyclic group which may be substituted” in R³,R⁴ and R⁵, (1) preferred examples are one or more groups selected from ahydroxyl group, a halogen atom, a cyano group, a nitro group, an alkylgroup having one to six carbon atoms which may be substituted, analkenyl group having two to six carbon atoms which may be substituted,an alkynyl group having two to six carbon atoms which may besubstituted, an alkoxy group having one to six carbon atoms which may besubstituted, an alkenyloxy group having two to six carbon atoms whichmay be substituted, an alkylthio group having one to six carbon atomswhich may be substituted, an alkenylthio group having two to six carbonatoms which may be substituted, an alkynylthio group having two to sixcarbon atoms which may be substituted, a substituted carbonyl group, anamino group which may be substituted, an alkylsulfonyl group having oneto six carbon atoms which may be substituted, an alkenylsulfonyl grouphaving two to six carbon atoms which may be substituted, analkynylsulfonyl group having two to six carbon atoms which may besubstituted, an alkylsulfinyl group having one to six carbon atoms whichmay be substituted, an alkenylsulfinyl group having two to six carbonatoms which may be substituted, an alkynylsulfinyl group having two tosix carbon atoms which may be substituted, a formyl group, a cycloalkylgroup having three to eight carbon atoms which may be substituted, acycloalkenyl group having three to eight carbon atoms which may besubstituted, a 5 to 14-membered non-aromatic heterocyclic group whichmay be substituted, an aromatic cyclic hydrocarbon group having six tofourteen carbon atoms which may be substituted and a 5 to 14-memberedaromatic heterocyclic group which may be substituted; (2) morepreferably, one or more groups selected from (1) a hydroxyl group, (2) ahalogen atom, (3) a cyano group, (4) a nitro group, (5) an alkyl grouphaving one to six carbon atoms, an alkenyl group having two to sixcarbon atoms or an alkynyl group having two to six carbon atoms, each ofwhich may be substituted with one or more groups selected from (i) ahydroxyl group, (ii) a cyano group, (iii) a halogen atom, (iv) analkylamino group having one to six carbon atoms, (v) a di(C₁₋₆alkyl)amino group, (vi) a C₂₋₆ alkenylamino group, (vii) a di(C₂₋₆alkenyl)amino group, (viii) an alkynylamino group having two to sixcarbon atoms, (ix) a di(C₂₋₆ alkynyl)amino group, (x) an N—C₁₋₆alkyl-N—C₂₋₆ alkenylamino group, (xi) an N—C₁₋₆ alkyl-N—C₂₋₆alkynylamino group, (xii) an N—C₂₋₆ alkenyl-N—C₂₋₆ alkynylamino group,(xiii) an aralkyloxy group, (xiv) a t-butyldimethylsilyloxy (TBDMS-oxy)group, (xv) a C₁₋₆ alkylsulfonylamino group, (xvi) a C₁₋₆alkylcarbonyloxy group, (xvii) a C₂₋₆ alkenylcarbonyloxy group, (xviii)a C₂₋₆ alkynylcarbonyloxy group, (xix) an N—C₁₋₆ alkylcarbamoyl group,(xx) an N—C₂₋₆ alkenylcarbamoyl group and (xxi) an N—C₁₋₆alkynylcarbamoyl group, (6) an alkoxy group having one to six carbonatoms, an alkenyloxy group having two to six carbon atoms or analkynyloxy group having two to six carbon atoms, each of which may besubstituted with one or more groups selected from (i) an alkylaminogroup having one to six carbon atoms, (ii) an aralkyloxy group and (iii)a hydroxyl group, (7) an alkylthio group having one to six carbon atoms,an alkenylthio group having two to six carbon atoms or an alkynylthiogroup having two to six carbon atoms, each of which may be substitutedwith one or more groups selected from (i) a hydroxyl group, (ii) anitrile group, (iii) a halogen atom, (iv) an alkylamino group having oneto six carbon atoms, (v) an aralkyloxy group, (vi) a TBDMS-oxy group,(vii) a C₁₋₆ alkylsulfonylamino group, (viii) a C₁₋₆ alkylcarbonyloxygroup and (ix) a C₁₋₆ alkylcarbamoyl group, (8) carbonyl groupsubstituted with a group selected from (i) an alkoxy group having one tosix carbon atoms, (ii) an amino group, (iii) an alkylamino group havingone to six carbon atoms, (iv) a di (C₁₋₆ alkyl)amino group, (v) analkenylamino group having two to six carbon atoms, (vi) a di(C₂₋₆alkenyl)amino group, (vii) an alkynylamino group having two to sixcarbon atoms, (viii) a di(C₂₋₆ alkynyl)amino group, (ix) an N—C₁₋₆alkyl-N—C₁₋₆ alkenylamino group, (x) an N—C₁₋₆ alkyl-N—C₂₋₆ alkynylaminogroup and (xi) an N—C₂₋₆ alkenyl-N—C₂₋₆ alkynylamino group, (9) an aminogroup which may be substituted with one or two groups selected from (i)an alkyl group having one to six carbon atoms, (ii) an alkenyl grouphaving two to six carbon atoms, (iii) an alkynyl group having two to sixcarbon atoms, (iv) an alkylsulfonyl group having one to six carbonatoms, (v) an alkenylsulfonyl group having two to six carbon atoms, (vi)an alkynylsulfonyl group having two to six carbon atoms, (vii) a C₁₋₆alkylcarbonyl group, (viii) a C₂₋₆ alkenylcarbonyl group and (ix) a C₂₋₆alkynylcarbonyl group, (10) an alkylsulfonyl group having one to sixcarbon atoms, (11) an alkenylsulfonyl group having two to six carbonatoms, (12) an alkynylsulfonyl group having two to six carbon atoms,(13) an alkylsulfinyl group having one to six carbon atoms, (14) analkenylsulfinyl group having two to six carbon atoms, (15) analkynylsulfinyl group having two to six carbon atoms, (16) a formylgroup, (17) a cycloalkyl group having three to eight carbon atoms orcycloalkenyl group having three to eight carbon atoms, each of which maybe substituted with one or more groups selected from (i) a hydroxylgroup, (ii) a halogen atom, (iii) a nitrile group, (iv) an alkyl grouphaving one to six carbon atoms, (v) an alkoxy group having one to sixcarbon atoms, (vi) a C₁₋₆ alkoxy-C₁₋₆ alkyl group and (vii) an aralkylgroup, (18) a 5 to 14-membered non-aromatic heterocyclic group which maybe substituted with one or more groups selected from (i) a hydroxylgroup, (ii) a halogen atom, (iii) a nitrile group, (iv) an alkyl grouphaving one to six carbon atoms, (v) an alkoxy group having one to sixcarbon atoms, (vi) a C₁₋₆ alkoxy-C₁₋₆ alkyl group and (vii) an aralkylgroup, (19) an aromatic cyclic hydrocarbon group having six to fourteencarbon atoms which may be substituted with one or more groups selectedfrom (i) a hydroxyl group, (ii) a halogen atom, (iii) a nitrile group,(iv) an alkyl group having one to six carbon atoms, (v) an alkoxy grouphaving one to six carbon atoms, (vi) a C₁₋₆ alkoxy-C₁₋₆ alkyl group and(vii) an aralkyl group, and (20) a 5 to 14-membered aromaticheterocyclic group which may be substituted with one or more groupsselected from (i) a hydroxyl group, (ii) a halogen atom, (iii) a nitrilegroup, (iv) an alkyl group having one to six carbon atoms, (v) an alkoxygroup having one to six carbon atoms, (vi) a C₁₋₆ alkoxy-C₁₋₆ alkylgroup and (vii) an aralkyl group; and (3) most preferably, one or moregroups selected from a hydroxyl group, a halogen atom (e.g., fluorineatom, chlorine atom, bromine atom or iodine atom), a cyano group, anitro group, an alkyl group having one to six carbon atoms (e.g., methylgroup, ethyl group, n-propyl group, iso-propyl group, n-butyl group,iso-butyl group, t-butyl group, n-pentyl group, i-pentyl group,neopentyl group or n-hexyl group), an alkenyl group having two to sixcarbon atoms (e.g., vinyl group, allyl group, 1-propenyl group orisopropenyl group), an alkynyl group having two to six carbon atoms(e.g., ethynyl group, 1-propynyl group, 2-propynyl group, butynyl group,pentynyl group or hexynyl group), an alkoxy group having one to sixcarbon atoms (e.g., methoxy group, ethoxy group, n-propoxy group,iso-propoxy group or n-butoxy group) and an alkenyloxy group having twoto six carbon atoms (e.g., vinyloxy group, allyloxy group, 1-propenyloxygroup or isopropenyloxy group)

Preferred embodiments of the compound represented by the formula (I)according to the present invention, a salt thereof or a solvate of themare not specifically limited, of which more preferred embodiments arecompounds wherein R⁴ is a 6-oxo-1,6-dihydropyridinyl group or a2-oxo-1,2-dihydropyridinyl group represented by the formula:

or the formula:

(wherein, R⁸ represents a group selected from the above-mentionedsubstituent group a, and the ring B represents a nitrogen-containing6-membered ring which may be substituted with one to four groupsselected from the above-mentioned substituent group a) or a 4-pyridylgroup which may have one or two substituents; or salts thereof orsolvates of that. The preferred embodiments of R⁸ are those mentionedabove.

The “salt” used in the present description is a salt formed from thecompound according to the present invention, of which apharmacologically acceptable salt is preferred. Preferred examplesthereof are a hydrohalogenic acid salt such as hydrofluoride,hydrochloride, hydrobromide or hydroiodide; an inorganic acid salt suchas sulfate, nitrate, perchlorate, phosphate, carbonates orhydrogencarbonate; an organic carboxylic acid salt such as acetate,trifluoroacetate, oxalate, maleate, tartrate, fumarate or citrate; anorganic sulfonic acid salt such as methanesulfonate,trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate,toluenesulfonate or camphorsulfonate; an amino acid salt such asaspartate or glutamate; a quaternary amine salt; an alkali metal saltsuch as sodium salt or potassium salt; an alkaline earth metal salt suchas magnesium salt or calcium salt. More preferred examples of the“pharmacologically acceptable salt” are hydrochloride and oxalate.

The “solvate” used in the present description is a solvate of thecompound according to the present invention or a salt thereof and is notspecifically limited. Preferably, the solvate is a hydrate, a solvatewith an alcohol such as methanol, ethanol, propanol, or isopropanol, asolvate with an ester such as ethyl acetate, a solvate with an ethersuch as methyl ether, ethyl ether or THF (tetrahydrofuran) or a solvatewith DMF (dimethylformamide), of which a hydrate or a solvate with analcohol such as methanol or ethanol is more preferred. A solvent forconstituting the solvate is preferably a pharmacologically acceptablesolvent.

Production Process

Typical production processes for the compounds represented by theformula (I) according to the present invention will be illustrated below. The “room temperature” as used hereinafter represents a temperaturefrom about 0° C. to about 40° C.

In the above formulae, Ar^(1a) represents an aromatic hydrocarbon cyclicgroup having six to fourteen carbon atoms which may be substituted or a5 to 14-membered aromatic heterocyclic group which may be substituted;X^(a) represents an alkyl group having one to six carbon atoms; andR^(1a) represents a 5 to 14-membered aromatic heterocyclic group havinga nitrogen atom at 4-position thereof and which may be substituted (suchas a 4-pyridyl group, a 4-pyrimidinyl group or a 4-pyridazinyl group).The compound (A3), which is provided as a raw material for theproduction of the compound represented by the above formula (I) of thepresent invention, can be produced through dealcoholization-condensationby reacting an aromatic carboxylate (A1) with a 4-methyl aromaticheterocyclic compound (A2) represented by the formula of R^(1a)-CH₃ in asolvent in the presence of a base. The base used varies depending on thestarting materials, solvent used, and so on in the production.Preferable bases include secondary amine metal salts such as lithiumbis(trimethylsilyl)amide and lithium diisopropylamide although notspecifically limited to as far as the reaction is not inhibited. Thesolvent used varies depending on, for example, the starting materialsand reagents used. Preferable solvents include ethers such astetrahydrofuran, dioxane, 1,2-dimethoxyethane and diethylene glycol,although not particularly limited insofar as the reaction is notinhibited and the starting materials are dissolved to a certain degree.The reaction temperature is generally −78° C. to room temperature,preferably around 0° C.

In the above formulae, Ar^(1b) and R^(1b) are the same as or differentfrom each other and each represents an aromatic hydrocarbon cyclic grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted; andX^(b) represents a halogen atom, an alkylsulfonyloxy group or anarylsulfonyloxy group. The compound (B3), which is provided as a rawmaterial for the production of the compound represented by the aboveformula (I) of the present invention, can be produced by this ProductionProcess B instead of Production Process A. That is, the compound (B3) isproduced by the condensation between an aromatic trialkylsilylcyanohydrin compound prepared from an aromatic aldehyde (B1) and thecompound (B2) represented by the formula of R^(1b)—CH₂X^(b) in thepresence of a base, followed by reacting with a fluorine compound tocause de(trialkylsilyl)cyanidation. As an agent for preparing anaromatic trialkylsilyl cyanohydrin from the compound (B1), atrialkylsilyl cyanide compound such as trimethylsilyl cyanide, ispreferably used. At this time, it is also preferable to use a metal saltsuch as zinc (II) iodide as a catalyst, allowing the reaction to proceedquickly. The base used varies depending on the starting materials,solvent used, and so on. Preferable bases include secondary amine metalsalts such as lithium bis(trimethylsilyl)amide or lithiumdiisopropylamide although not specifically limited to as far as thereaction is not inhibited. The fluorine compound used varies dependingon the starting materials, solvents used, and so on. Preferable fluorinecompounds include hydrofluoric acid and hydrofluoride of amine, morepreferably tetrabutylammonium fluoride although not specifically limitedto as far as the reaction is not inhibited. The solvent used variesdepending on the starting materials, reagents, and so on. Preferableexamples of the solvent used, although not specifically limited to asfar as the starting materials are dissolved to a certain degree, includeethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane ordiethylene glycol. The reaction temperature is preferably −78° C. toroom temperature.

In the above formulae, Ar^(1c) and R^(1c) are the same as or differentfrom each other and each represents an aromatic hydrocarbon cyclic grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted.3-(Dimethylamino)-2-propen-1-one derivative (C2) is a raw material forthe production of the compound (I) of the present invention. Thecompound (C2) can be produced by allowing N,N-dimethylformamidedimethylacetal to act on active methylene of the compound (C1) producedin Production Process A or B. Most preferable is to perform thisreaction without any solvent. However, a preferable result can beobtained even though the compound (C1) is diluted with a solvent (suchas N,N-dimethylformamide, tetrahydrofuran, dioxane, N-methylpyrrolidone,benzene or toluene) that dissolves the starting materials to a certaindegree without inhibiting the reaction. The reaction temperature isgenerally room temperature to 120° C., preferably around 100° C.

In the above formulae, Ar^(1d) and R^(1d) are the same as or differentfrom each other and each represents an aromatic hydrocarbon cyclic grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted; andR^(2d) and R^(3d) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted. The compound (D3) of the presentinvention can be produced by allowing a guanidine derivative (D2) toreact with 3-(dimethylamino)-2-propen-1-one derivative (D1) produced byProduction Process C in the presence of a base. The guanidine derivative(D2) used may form a salt with an acid such as hydrochloric acid,hydrobromic acid, sulfuric acid or acetic acid. The base used variesdepending on the starting materials, solvent used, and so on. Preferableexamples of the base include an alkali metal carbonate such as potassiumcarbonate or sodium carbonate, or an alkali metal alkoxide such assodium methoxide, sodium ethoxide or potassium t-butoxide although notspecifically limited to as far as the reaction is not inhibited. Thesolvent used varies depending on the starting materials, reagents, andso on. Preferable examples of the solvent include N,N-dimethylformamide,N-methylpyrrolidone, dimethylsulfoxide and ethanol, although notspecifically limited to as far as the reaction is not inhibited and thestarting materials and bases are dissolved to a certain degree. Thereaction temperature is preferably room temperature to 120° C., morepreferably around 70° C.

In the above formulae, Ar^(1e), R^(1e) and R^(4e) are the same as ordifferent from each other and each represents an aromatic hydrocarboncyclic group having six to fourteen carbon atoms which may besubstituted or a 5 to 14-membered aromatic heterocyclic group which maybe substituted; and R^(2e) and R^(3e) are the same as or different fromeach other and each represents a hydrogen atom, an alkyl group havingone to six carbon atoms which may be substituted, an alkenyl grouphaving two to six carbon atoms which may be substituted, an alkynylgroup having two to six carbon atoms which may be substituted, acycloalkyl group having three to eight carbon atoms which may besubstituted, a cycloalkenyl group having three to eight carbon atomswhich may be substituted, a 5 to 14-membered non-aromatic heterocyclicgroup which may be substituted, an aromatic hydrocarbon cyclic grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted. Thecompound (E4) of the present invention can be produced by allowing analdehyde (E2) and a guanidine derivative (E3) to react with the compound(E1) produced by the above Production Process A or B in the presence ofthe base, followed by aromatizing with an oxidant. The guanidinederivative (E3) used may form a salt with an acid such as hydrochloricacid, hydrobromic acid, sulfuric acid or acetic acid. The base usedvaries depending on the starting materials, solvent used, and so on.Preferably, although not specifically limited to as far as the reactionis not inhibited, the base used may be an alkali metal alkoxide such assodium methoxide, sodium ethoxide or potassium t-butoxide, oralternatively an alkali metal carbonate such as potassium carbonate orsodium carbonate. Examples of oxidant used include manganese compoundssuch as active manganese dioxide, quinones such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and sulfur. The solvent usedis not specifically limited to as far as the reaction is not inhibitedand the starting materials and intermediates are dissolved to a certaindegree. Examples of the solvents may include ethanol, methanol,tetrahydrofuran, dichloromethane, dichloroethane, chloroform,N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, and mixedsolvents thereof. The reaction temperature is preferably 0° C. to 120°C.

In the above formulae, Ar^(1f) and R^(1f) are the same as or differentfrom each other and each represents an aromatic hydrocarbon cyclic grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted; andR^(2f) and R^(3f) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted. The compound (F5) of the presentinvention and the compound (F6), which is provided as a raw material forthe production of the compound (I) of the present invention, can beproduced by Steps F-1 and F-2 in Production Process F.Step F-1: This step is to produce the compound (F3) bydehydration-condensation between the compound (F1) and the aldehydecompound (F2) in the presence of a base. Preferable examples of the baseused in the reaction include alkali metal alkoxides such as sodiummethoxide, sodium ethoxide or potassium t-butoxide. Alternatively,alkali metal carbonates such as potassium carbonate or sodium carbonatemay be used. The reaction is carried out in a solvent which is notspecifically limited to as far as the reaction is not inhibited and thestarting materials and intermediates are dissolved to a certain degree.The solvents may include ethanol, methanol, tetrahydrofuran,dichloromethane, chloroform, N,N-dimethylformamide, N-methylpyrrolidone,dimethylsulfoxide, and mixed solvents thereof. The reaction is carriedout at a temperature of 0° C. to 120° C.Step F-2: This step is to produce the pyrimidine derivative (F5) byreacting the compound (F3) obtained in Step F-1 with the guanidinederivative (F4) in the presence of the base, followed by aromatizingwith an oxidant. The guanidine derivative (F4) used may form a salt withan acid such as hydrochloric acid, hydrobromic acid, sulfuric acid oracetic acid. Preferable examples of the base used in the reactioninclude alkali metal alkoxides such as sodium methoxide, sodium ethoxideor potassium t-butoxide. Alternatively, alkali metal carbonates such aspotassium carbonate or sodium carbonate may be used. Examples of theoxidant used in the reaction include manganese compounds such as activemanganese dioxide, quinones such as2,3-dichloro-5,6-dicyanao-1,4-benzoquinone, and sulfur. The reaction iscarried out in a solvent which is not specifically limited to as far asthe reaction is not inhibited and the starting materials andintermediates are dissolved to a certain degree. The solvents mayinclude ethanol, methanol, tetrahydrofuran, dichloromethane, chloroform,N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, and mixedsolvents thereof. The reaction temperature is 0° C. to 120° C.Alternatively, in Step F-1, even if the guanidine derivative (F4) isprovided in the reaction mixture from the be ginning of the reaction,followed by the aromatization with the oxidant, the pyrimidinederivative (5) can be produced without isolating the compound (F3).Furthermore, in step F-2, the reaction between the compound (F3) and theguanidine derivative (F4) in the presence of a base, the reaction (underheating) was carried out for a long period of two to seven days undermoisture conditions, followed by an oxidative reaction, to give thepyrimidinone derivative (F6).

In the above formulae, Ar^(1g) and R^(1g) are the same as or differentfrom each other, and each represents an aromatic hydrocarbon cyclicgroup having six to fourteen carbon atoms which may be substituted or a5 to 14-membered aromatic heterocyclic group which may be substituted;and X^(g) represents a halogen atom, an alkylsulfonyloxy group or anarylsulfonyloxy group. The present production method is an alternativemethod for the synthesis of the compound (F3) in Production Process Fdescribed above. That is, the method includes the step of allowingcyanomethylphosphonic acid diester to react with the compound (G1) inthe presence of a base and a palladium catalyst, followed bydephosphorylation-condensation with an aldehyde compound represented bythe formula of Ar^(1g)—CHO to produce a compound (G2). The base used inthe reaction is preferably sodium hydride, and the palladium catalystused is preferably tetrakis(triphenylphosphine)palladium (O),respectively. Preferably, the reaction solvents include ethers such asdimethoxyethane, diethyl ether or tetrahydrofuran. The reaction iscarried out at a temperature of 0° C. to 120° C.

In the above formulae, Ar^(1h) and R^(1h) are the same as or differentfrom each other and each represents an aromatic hydrocarbon cyclic grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted; R²hand R³h are the same as or different from each other and each representsa hydrogen atom, an alkyl group having one to six carbon atoms which maybe substituted, an alkenyl group having two to six carbon atoms whichmay be substituted, an alkynyl group having two to six carbon atomswhich may be substituted, a cycloalkyl group having three to eightcarbon atoms which may be substituted, a cycloalkenyl group having threeto eight carbon atoms which may be substituted, a 5 to 14-memberednon-aromatic heterocyclic group which may be substituted, an aromatichydrocarbon cyclic group having six to fourteen carbon atoms which maybe substituted or a 5 to 14-membered aromatic heterocyclic group whichmay be substituted; and X^(h) represents an alkyl group having one tosix carbon atoms. The present production method is another syntheticmethod for the compound (F6) in Production Process F.Step H-1: This step is to produce the compound (H3) bydehydration-condensation between the compound (H1) and the compound (H2)using carboxylic anhydride in the presence of a base. Examples of thebase used in the reaction include amines such as triethylamine,pyrrolidine, piperidine or diisopropylethylamine. The carboxylicanhydride is preferably acetic anhydride. The reaction is carried out atroom temperature to 120° C.Step H-2: This step is to produce the pyrimidinone derivative (H5) as araw material for the production of the compound represented by the aboveformula (I) of the present invention, by reacting the compound (H3)obtained in Step H-1 with the guanidine derivative (H4) in the presenceof a base, followed by aromatization with an oxidant. The guanidinederivative (H4) to be used may form a salt with an acid such ashydrochloric acid, hydrobromic acid, sulfuric acid or acetic acid.Preferable examples of the base to be used in the reaction includealkali metal alkoxides such as sodium methoxide, sodium ethoxide orpotassium t-butoxide. Alternatively, an alkali metal carbonate such aspotassium carbonate or sodium carbonate may be used. Examples of theoxidant to be used in the reaction include manganese compounds such asactive manganese dioxide; quinones such as2,3-dichloro-5,6-dicyanao-1,4-benzoquinone; and sulfur. The reaction iscarried out in a solvent which does not inhibit the reaction and whichdissolves the starting materials and intermediates to a certain degree.Examples of the solvents include ethanol, methanol, tetrahydrofuran,dichloromethane, chloroform, N,N-dimethylformamide, N-methylpyrrolidone,dimethylsulfoxide, and mixed solvents thereof. The reaction is performedin temperatures of 0° C. to 120° C.

In the above formulae, Ar^(1i) and R^(1i) are the same as or differentfrom each other and each represents an aromatic hydrocarbon cyclic grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted; R^(2i)and R^(3i) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted; R^(4i) represents an oxygen atom whichmay be substituted; and X^(i) represents a halogen atom. The compounds(I2) and (I3) of the present invention can be produced by ProductionProcess I.

Step I-1: This step is to produce a 4-halogenopyrimidine derivative (I2)of the present invention from the pyrimidinone derivative (I1) obtainedin Production Process F or H by converting the oxo group of thepyrimidinone derivative (I1) into a halogen atom. The reaction iscarried out in the absence of a solvent or in a suspension with asolvent such as acetonitrile, dioxane or tetrahydrofuran by allowing ahalogenating agent such as phosphorous oxychloride or, phosphorousoxybromide at a temperature of 70° C. to 120° C. The reaction can beaccelerated by the addition of a tertiary amine such as dimethylaniline,diisopropylethylamine or tripropylamine; a quaternary ammonium salt suchas tetraethylammonium chloride; or N,N-dimethylformamide.

Step I-2: This step is to produce a 4-alkoxypyrimidine derivative (I3)of the present invention from the 4-halogenopyrimidine derivative (I2)obtained in Step I-1 described above by allowing an alkali metalalkoxide to act on the 4-chloropyrimidine derivative to convert thehalogen atom at position 4 thereof into an alkoxy group. The alkalimetal alkoxide can be prepared by allowing a base or an alkali metal toact on an alcohol in a solvent or in the absence of the solvent. Thealkali metal used is preferably sodium or potassium. The base used inthe reaction varies depending on the starting materials, solvents used,and so on. Preferable bases include alkali metal hydride such as sodiumhydride and so on, although not specifically limited to as far as thereaction is not inhibited. Alternatively alkali metal alkoxides such assodium methoxide, sodium ethoxide or potassium t-butoxide may be used.The solvent used varies depending on the starting materials, reagents,and so on. Preferably, although not specifically limited to as far asthe reaction is not inhibited and the starting materials and bases aredissolved to a certain degree, examples of the solvents includeN,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, alcoholssuch as methanol or ethanol; ethers such as tetrahydrofuran or1,4-dioxane; and mixed solvents thereof. The reaction temperature ispreferably room temperature to 120° C.

In the above formulae, Ar^(1j) and R^(1j) are the same as or differentfrom each other and each represents an aromatic hydrocarbon cyclic grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted; R^(2j)and R^(3j) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted; and R^(4j) represents an alkyl groupwhich may be substituted. The compounds (J4) of the present inventioncan be produced by Production Process J.

Step J-1: This step is to produce the compound (J2) by allowing aGrignard reagent to react with the compound (J1) obtained in Step H-1ofthe Production Process H described above. The reaction is carried out ina solvent which does not inhibit the reaction and dissolves the startingmaterials and intermediates to a certain degree. The solvents mayinclude ethers such as tetrahydrofuran, diethyl ether ordimethoxyethane. The reaction temperature is −78° C. to roomtemperature.Step J-2: This step is to produce the pyrimidine derivative (J4) of thepresent invention by reacting the compound (J2) obtained in Step J-1with the guanidine derivative (J3) in the presence of a base, followedby aromatization with an oxidant. The guanidine derivative (J3) to beused may form a salt with an acid such as hydrochloric acid, hydrobromicacid, sulfuric acid or acetic acid. Preferable examples of the base tobe used in the reaction include alkali metal alkoxides such as sodiummethoxide, sodium ethoxide or potassium t-butoxide. Alternatively, analkali metal carbonate such as potassium carbonate or sodium carbonatemay be used. Examples of the oxidant to be used in the reaction include:manganese compounds such as active manganese dioxide; quinones such as2,3-dichloro-5,6-dicyanao-1,4-benzoquinone; and sulfur. The reaction iscarried out in a solvent which does not inhibit the reaction and whichdissolves the starting materials and intermediates to a certain degree.Examples of the solvents include ethanol, methanol, tetrahydrofuran,dichloromethane, chloroform, N,N-dimethylformamide, N-methylpyrrolidone,dimethylsulfoxide, and mixed solvents thereof. The reaction is performedin the temperature of 0° C. to 120° C.

In the above formulae, Ar^(1k) represents an aromatic hydrocarbon cyclicgroup having six to fourteen carbon atoms which may be substituted or a5 to 14-membered aromatic heterocyclic group which may be substituted;R^(2k) and R^(3k) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted; R^(4k) represents a hydrogen atom, acyano group, an alkyl group having one to six carbonatoms which may besubstituted, an alkenyl group having two to six carbon atoms which maybe substituted, an alkynyl group having two to six carbon atoms whichmay be substituted, an aromatic hydrocarbon cyclic group having six tofourteen carbon atoms which may be substituted, a 5 to 14-memberedaromatic heterocyclic group which may be substituted, a nitrogen atomwhich may be substituted, an oxygen atom which may be substituted or asulfur atom which may be substituted; the ring A^(k) represents apyridyl group, a pyrimidinyl group, a pyrazinyl group or a pyridazinylgroup; the ring A′^(k) represents a dihydrooxopyridinyl group, adihydrooxopyrimidinyl group, a dihydrooxopyrazinyl group or adihydrooxopyridazinyl group; and X^(k) represents a halogen atom. Thisstep is to produce the 5-(α-oxo nitrogen-containingheterocyclyl)pyrimidine (K2) of the present invention by convertinghalogen atom (X^(k)) in 5-(α-halogeno nitrogen-containingheteroaryl)pyrimidine (K1) into 4-methoxybenzyloxy group whilesubstituting the halogen atom (X^(k)) of 5-(α-halogenonitrogen-containing heteroaryl)pyrimidine (K1) with4-methoxybenzylalkoxide, followed by treatment with an acid. The4-methoxybenzylalkoxide is prepared using an alkali metal such as sodiumor potassium or a base such as sodium hydride in the absence of asolvent or by dilution with a solvent such as N,N-dimethylformamide ordimethylsulfoxide at a temperature of room temperature to 120° C. Theacid used in the reaction may be trifluoroacetic acid, hydrochloricacid, bromic acid, or the like. The reaction is carried out in theabsence of a solvent or by dilution with a solvent such asdichloromethane, dichloroethane or tetrahydrofuran at a temperature ofroom temperature to 150° C.

In the above formulae, Ar^(1l) represents an aromatic hydrocarbon cyclicgroup having six to fourteen carbon atoms which may be substituted or a5 to 14-membered aromatic heterocyclic group which may be substituted;R^(2l) and R^(3l) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted; R^(4l) represents a hydrogen atom, acyano group, an alkyl group having one six carbon atoms which may besubstituted, an alkenyl group having two to six carbon atoms which maybe substituted, an alkynyl group having two to six carbon atoms whichmay be substituted, an aromatic hydrocarbon cyclic group having six tofourteen carbon atoms which may be substituted, a 5 to 14-memberedaromatic heterocyclic group which may be substituted, a nitrogen atomwhich may be substituted, an oxygen atom which may be substituted or asulfur atom which may be substituted; R⁵¹ represents an alkyl grouphaving one to six carbon atoms which may be substituted; the ring A^(l)represents a pyridyl group, a pyrimidinyl group, a pyrazinyl group or apyridazinyl group; and the ring A′^(l) represents a dihydrooxopyridinylgroup, a dihydrooxopyrimidinyl group, a dihydrooxopyrazinyl group or adihydroxoopyridazinyl group. This step is to produce the 5-(α-oxonitrogen-containing heterocyclyl)pyrimidine (L2) of the presentinvention by hydrolyzing the alkyl group of 5-(α-alkoxynitrogen-containing heteroaryl)pyrimidine (L1). The reaction is carriedout in an aqueous solution of a mineral acid such as hydrochloric acid,hydrobromic acid or sulfuric acid, or in a mixed solvent of water withacetic acid or the like at a temperature of room temperature to 120° C.

In the above formulae, Ar^(1m) represents an aromatic hydrocarbon cyclicgroup having six to fourteen carbon atoms which may be substituted or a5 to 14-membered aromatic heterocyclic group which may be substituted;R^(2m) and R^(3m) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted; R^(4m) represents a hydrogen atom, acyano group, an alkyl group having one to six carbon atoms which may besubstituted, an alkenyl group having two to six carbon atoms which maybe substituted, an alkynyl group having two to six carbon atoms whichmay be substituted, an aromatic hydrocarbon cyclic group having six tofourteen carbon atoms which may be substituted, a 5 to 14-memberedaromatic heterocyclic group which may be substituted, a nitrogen atomwhich may be substituted, an oxygen atom which may be substituted or asulfur atom which may be substituted; R^(5m) represents an alkyl groupwhich may be substituted, an alkenyl group which may be substituted oran alkynyl group which may be substituted; and the ring A^(m) representsa dihydrooxopyridinyl group, a dihydrooxopyrimidinyl group, adihydrooxopyrazinyl group or a dihydrooxopyridazinyl group. This step isto produce the compound (M3) of the present invention by introducing asubstituent to the nitrogen atom on the ring A^(m) of5-(α-oxonitrogen-containing heterocyclyl)pyrimidine (M1) The reaction is carriedout through the reaction with a halogenatedalkyl compound or the like ina solvent in the presence of abase. The bases include sodiummethoxide,sodium ethoxide, potassium t-butoxide, sodium hydride, sodium hydroxide,potassium hydroxide, sodium bicarbonate, sodium carbonate and potassiumcarbonate. The solvents include alcohols such as methanol or ethanol,ethers such as tetrahydrofuran, dioxane, dimethoxyethane or diethyleneglycol dimethyl ether, N,N-dimethylformamide, dimethylsulfoxide,N-methylpyrrolidone, and mixed solvents thereof. The reaction is carriedout at a temperature of 0° C. to 100° C.

In the above formulae, R^(n) represents an alkyl group having one to sixcarbon atoms which may be substituted; the ring A^(n) represents apyridyl group, a pyrimidinyl group, a pyrazinyl group or a pyridazinylgroup; and X^(1n) and X^(2n) are the same as or different from eachother and each represents a halogen atom. This step is to produce anα-alkoxy nitrogen-containing heteroaryl compound (N2) as a raw materialfor the production of the compound represented by the formula (I) of thepresent invention by allowing alkali metal alkoxide to react with anα-halogeno nitrogen-containing heteroaryl compound (N1) in a solvent.The alkali metal alkoxide is prepared by allowing an alkali metal orbase to react with an alcohol in a solvent or in the absence of thesolvent. Preferably, for example, the alkali metal used is sodium orpotassium. The base used in the reaction varies depending on thestarting materials, solvents used, and so on. Preferable bases includean alkali metal hydride such as sodium hydride, although notspecifically limited to as far as the reaction is not inhibited.Alternatively, alkali metal alkoxides such as sodium methoxide, sodiumethoxide or potassium t-butoxide may be used. The solvent used variesdepending on the starting materials, reagents, and so on. Preferably,although not specifically limited to as far as the reaction is notinhibited and the starting materials and bases are dissolved to acertain degree, the solvents include alcohols such asN,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, alcoholssuch as methanol or ethanol, ethers such as tetrahydrofuran or1,4-dioxane, and mixed solvents thereof. The reaction temperature ispreferably room temperature to 120° C.

In the above formulae, R^(5o) represents an aromatic hydrocarbon cyclicgroup having six to fourteen carbon atoms which may be substituted or a5 to 14-membered aromatic heterocyclic group which may be substituted;X^(o) represents a halogen atom; and Y^(o) represents an alkyl grouphaving one to six carbon atoms. A tin reagent (O2) as a raw material forthe production of the compound represented by the above formula (I) ofthe present invention can be produced by lithiating the compound (O1)and then allowing a halogenotrialkyltin to react with the lithiatedcompound. In the lithiation reaction, it is preferable to usealkyllithium such as n-butyllithium, s-butyllithium or t-butyllithium.The halogeno trialkyltin used varies depending on the startingmaterials, solvents used, and so on. Preferably, tributyltin chloride,trimethyltin chloride, triethyltin bromide, or the like may be proposed,although not specifically limited to as far as the reaction is notinhibited. The solvent used in the reaction varies depending on thestarting materials, reagents, and so on. Preferably, the solventsinclude ethers such as tetrahydrofuran and diethyl ether, orhydrocarbons such as hexane and heptane, and mixed solvents thereof,although not specifically limited to as far as the reaction is notinhibited and the starting material is dissolved to a certain degree.The reaction temperature is preferably −100° C. to room temperature.

In the above formulae, Ar^(1p) represents an aromatic hydrocarbon cyclicgroup having six to fourteen carbon atoms which may be substituted or a5 to 14-membered aromatic heterocyclic group which may be substituted. A3-(dimethylamino)-2-propen-1-one derivative (P2) as a raw material forthe production of the compound represented by the above formula (I) ofthe present invention can be produced by allowing N,N-dimethylformamidedimethylacetal to react with the compound (P1). Most preferably, thereaction is carried out in the absence of a solvent. Alternatively, apreferable result can be also obtained by dilution with a solvent whichdissolves starting materials to some degree without inhibiting thereaction (e.g., N,N-dimethylformamide, tetrahydrofuran, dioxane,N-methylpyrrolidone, benzene, or toluene). The reaction temperature isgenerally room temperature to 120° C., preferably around 100° C.

In the above formulae, Ar^(1q) represents an aromatic hydrocarbon cyclicgroup having six to fourteen carbon atoms which may be substituted or a5 to 14-membered aromatic heterocyclic group which may be substituted;and R^(2q) and R^(3q) are the same as or different from each other andeach represents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted. This step is to produce a pyrimidinederivative (Q3) as a raw material for the production of the compoundrepresented by the above formula (I) of the present invention byallowing a guanidine derivative (Q2) to react with the3-(dimethylamino)-2-propen-1-one derivative (Q1) obtained fromProduction Process P described above. The guanidine derivative (Q2) usedmay form a salt with an acid such as hydrochloric acid, hydrobromicacid, sulfuric acid or acetic acid. The base used varies depending onthe starting materials, solvents used, and so on. Preferably, althoughnot specifically limited to as far as the reaction is not inhibited, thebase is alkali metal carbonate such as potassium carbonate or sodiumcarbonate, or alternatively alkali metal alkoxide such as sodiummethoxide, sodium ethoxide or potassium t-butoxide. The solvent usedvaries depending on the starting materials, reagents, and so on.Preferable examples of the solvent include N,N-dimethylformamide,N-methylpyrrolidone, dimethylsulfoxide and ethanol although notspecifically limited to as far as the reaction is not inhibited and thestarting materials and bases are dissolved to a certain degree. Thereaction temperature is preferably room temperature to 120° C., morepreferably around 100° C.

In the above formulae, A^(1r) and R^(4r) are the same as or differentfrom each other and each represents an aromatic hydrocarbon cyclic grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted; andR^(2r) and R^(3r) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted. The compound (R4) as a raw material forthe production of the compound represented by the above formula (I) ofthe present invention can be produced by allowing the aldehyde (R2) andthe guanidine derivative (R3) to react with the compound (R1) in thepresence of a base, followed by aromatizing with an oxidant. Theguanidine derivative (R3) to be used may form a salt with an acid suchas hydrochloric acid, hydrobromic acid, sulfuric acid or acetic acid.The base used varies depending on the starting materials, the solvent tobe used, and so on. Preferably, although not specifically limited to asfar as the reaction is not inhibited, the base to be used may be analkali metal alkoxide such as sodium methoxide, sodium ethoxide orpotassium t-butoxide, or alternatively an alkali metal carbonate such aspotassium carbonate or sodium carbonate. Examples of the oxidant to beused include: manganese compounds such as active manganese dioxide;quinones such as 2,3-dichloro-5,6-dicyanao-1,4-benzoquinone; and sulfur.The solvent to be used is not specifically limited to as far as thereaction is not inhibited and the starting materials and intermediatesare dissolved to a certain degree. Examples of the solvents includeethanol, methanol, tetrahydrofuran, dichloromethane, dichloroethane,chloroform, N,N-dimethylformamide, N-methylpyrrolidone,dimethylsulfoxide, and mixed solvents thereof. The reaction temperatureis preferably 0° C. to 120° C.

In the above formulae, Ar^(1s) and R^(1s) are the same as or differentfrom each other and each represents an aromatic hydrocarbon cyclic grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted; R^(2s)and R^(3s) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted; R^(4S) represents a hydrogen atom, anaromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted; and X^(S) represents a halogen atom. Thecompound (S3) of the present invention can be produced by ProductionProcess S.Step S-1: This step is to produce a 5-halogenopyrimidine derivative (S2)by halogenation at 5-position of the pyrimidine ring of the pyrimidinederivative (S1) obtained by Production Process Q or R described aboveusing a halogenating agent in a solvent. The halogenating agent used ispreferably N-bromosuccinimide, bromine, or the like. The solvent usedvaries depending on the starting materials, reagents, and so on.Preferably, although not specifically limited to as far as the reactionis not inhibited and the starting materials are dissolved to a certaindegree, the solvents include alcohols such as methanol or ethanol;ethers such as tetrahydrofuran, dioxane, dimethoxyethane ordiethyleneglycol dimethylether; N,N-dimethylformamide; andN-methylpyrrolidinone. The reaction temperature is generally −20° C. toroom temperature.Step S-2: This step is to produce the pyrimidine derivative (S3) of thepresent invention by allowing a tin reagent or the like, such as thecompound (O2) obtained in Production Process O, to react with the5-halogenopyrimidine derivative (S2) obtained in the production step S-1in a solvent in the presence of a palladium catalyst. The palladiumcatalyst used varies depending on the starting materials, solvents used,and so on. Preferably, although not specifically limited to as far asthe reaction is not inhibited, the palladium catalysts includedichlorobis(triphenylphosphine)palladium (II), palladium (II) acetate,tetrakis(triphenylphosphine)palladium (0), andtris(dibenzylideneacetone)dipalladium (0). The solvent used variesdepending on the starting materials, reagents, and so on. Preferably,although not specifically limited to as far as the reaction is notinhibited and the starting materials are dissolved to a certain degree,the solvents include alcohols such as methanol or ethanol; ethers suchas tetrahydrofuran, dioxane, dimethoxyethane or diethyleneglycoldimethylether; toluene; xylene; N,N-dimethylformamide; andN-methylpyrrolidinone. The reaction temperature is generally roomtemperature to 150° C., preferably around 100° C.

In the above formulae, Ar^(1t) represents an aromatic hydrocarbon cyclicgroup having six to fourteen carbon atoms which may be substituted or a5 to 14-membered aromatic heterocyclic group which may be substituted;R^(2t) and R^(3t) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted, a 5 to 14-membered aromatic heterocyclic groupwhich may be substituted, an acyl group having one to six carbon atomswhich may be substituted or an alkylsulfonyl group having one to sixcarbon atoms which may be substituted; R^(4t) represents a hydrogenatom, a halogen atom, a cyano group, an alkyl group having one to sixcarbon atoms which may be substituted, an alkenyl group having two tosix carbon atoms which may be substituted, an alkynyl group having twoto six carbon atoms which may be substituted, an aromatic hydrocarboncyclic group having six to fourteen carbonatoms which may besubstituted, a 5 to 14-membered aromatic heterocyclic group which may besubstituted, a nitrogen atom which may be substituted, an oxygen atomwhich may be substituted or a sulfur atom which may be substituted;R^(5t) represents an alkenyl group having two to six carbon atoms whichmay be substituted, an aromatic hydrocarbon cyclic group having six tofourteen carbon atoms or a 5 to 14-membered aromatic heterocyclic groupwhich may be substituted; and the ring A^(t) represents adihydrooxopyridinyl group, a dihydrooxopyrimidinyl group, adihydrooxopyrazinyl group or a dihydrooxopyridazinyl group. The compound(T2) of the present invention can be produced by the reaction betweenthe compound (T1) and a boron reagent in a solvent in the presence of abase and a copper catalyst. The base used in the reaction variesdepending on the starting materials, solvent used, and so on in theproduction. Preferably, although not specifically limited to as far asthe reaction is not inhibited, the bases include tertiary amines such aspyridine, diisopropylethylamine or triethylamine. The copper catalystused varies depending on the starting materials, solvent used, and so onin the production. Preferably, although not specifically limited to asfar as the reaction is not inhibited, the copper catalysts includedivalent copper compounds such as copper acetate, copper bromide orcopper sulfate, and copper acetate is more preferred. The solvent usedvaries depending on the starting materials, reagents, and so on in theproduction. Preferably, although not specifically limited to as far asthe reaction is not inhibited and the starting materials are dissolvedto a certain degree, the solvents include N,N-dimethylformamide,tetrahydrofuran, ethylacetate, and dichloromethane dioxane. The reactiontemperature is preferably room temperature to 120° C.

In the above formulae, Ar^(1u) represents an aromatic hydrocarbon cyclicgroup having six to fourteen carbon atoms which may be substituted or a5 to 14-membered aromatic heterocyclic group which may be substituted;R^(2u) and R^(3u) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl having two to six carbonatoms group which may be substituted, an alkynyl group having two to sixcarbon atoms which may be substituted, a cycloalkyl group having threeto eight carbon atoms which may be substituted, a cycloalkenyl grouphaving three to eight carbon atoms which may be substituted, a 5 to14-membered non-aromatic heterocyclic group which may be substituted, anaromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted, a 5 to 14-membered aromatic heterocyclic groupwhich may be substituted, an acyl group having one to six carbon atomswhich may be substituted or an alkylsulfonyl group having one to sixcarbon atoms which may be substituted; R^(4u) represents a hydrogenatom, a cyano group, an alkyl group having one to six carbon atoms whichmay be substituted, an alkenyl group having two to six carbon atomswhich may be substituted, an alkynyl group having two to six carbonatoms which may be substituted, an aromatic hydrocarbon cyclic grouphaving six to fourteen carbon atoms which may be substituted, a 5 to14-membered aromatic heterocyclic group which may be substituted, anitrogen atom which may be substituted or an oxygen atom which may besubstituted; R^(5u) represents a nitrogen atom which may be substituted,an oxygen atom which may be substituted or a sulfur atom which may besubstituted; the ring A^(u) represents a pyridyl group, a pyrimidinylgroup, a pyrazinyl group or a pyridazinyl group; and X^(u) represents ahalogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group. Thecompound (U2) of the present invention can be produced by the reactionbetween the compound (U1) and a nucleophilic reagent in a solvent or inthe absence of the solvent. The nucleophilic reagent used in thereaction is primary or secondary amine or alkali metal alkoxide. Thealkali metal alkoxide is prepared by allowing an alkali metal or base toreact with alcohol in a solvent or in the absence of the solvent.Preferably, an alkali metal used in the preparation of the alkali metalalkoxide is sodium or potassium. The base used in the preparation of thealkali metal alkoxide varies depending on the starting materials,solvents used, and so on in the production. Preferably, although notspecifically limited to as far as the reaction is not inhibited, thebase is an alkali metal hydride such as sodium hydride, or alternativelyalkali metal alkoxide such as sodium methoxide, sodium ethoxide orpotassium t-butoxide. The solvent used varies depending on the startingmaterials, reagents, and so on. Preferably, although not specificallylimited to as far as the reaction is not inhibited and the startingmaterials and reagents are dissolved to a certain degree, the solventsinclude N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide,alcohols such as methanol or ethanol, ethers such as tetrahydrofuran,1,2-dimethoxyethane or 1,4-dioxane, water, and a mixed solvent thereof.The reaction temperature is preferably room temperature to 200° C.

In the above formulae, Ar^(1v) represents an aromatic hydrocarbon cyclicgroup having six to fourteen carbon atoms which may be substituted or a5 to 14-membered aromatic heterocyclic group which may be substituted;R^(2v) and R^(3v) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted, a 5 to 14-membered aromatic heterocyclic groupwhich may be substituted, an acyl group having one to six carbon atomswhich may be substituted or an alkylsulfonyl group having one to sixcarbon atoms which may be substituted; R^(4v) represents a hydrogenatom, a halogen atom, a cyano group, an alkyl group having one to sixcarbon atoms which may be substituted, an alkenyl group having two tosix carbon atoms which may be substituted, an alkynyl group having twoto six carbon atoms which may be substituted, an aromatic hydrocarboncyclic group having six to fourteen carbon atoms which may besubstituted, a 5 to 14-membered aromatic heterocyclic group which may besubstituted, a nitrogen atom which may be substituted, an oxygen atomwhich may be substituted or a sulfur atom which may be substituted;R^(5v) represents an alkyl group having one to six carbon atoms; thering A^(v) represents a pyridyl group, a pyrimidynyl group, a pyrazinylgroup, a pyridazinyl group, a dihydrooxopyridinyl group, adihydrooxopyrimidinyl group, a dihydrooxopyrazinyl group or adihydrooxopyridazinyl group; and B^(v) represents an alkyl group havingone to six carbon atoms which may be substituted, an alkenyl grouphaving two to six carbon atoms which may be substituted, an alkynylgroup having two to six carbon atoms which may be substituted, acycloalkyl group having three to eight carbon atoms which may besubstituted, a cycloalkenyl group having three to eight carbon atomswhich may be substituted, a 5 to 14-membered non-aromatic heterocyclicgroup which may be substituted, an aromatic hydrocarbon cyclic grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted. Thecompound (V2) of the present invention can be produced by allowing abase to react with the compound (V1) in a solvent. The base used in thereaction varies depending on the starting materials, solvent used, andso on. Preferably, although not specifically limited to as far as thereaction is not inhibited, the base is alkali metal hydroxide such assodium hydroxide or potassium hydroxide. The solvent used variesdepending on the starting materials, reagents, and so on. Preferably,although not specifically limited to as far as the reaction is notinhibited and the starting materials are dissolved to a certain degree,the solvents include methanol, tetrahydrofuran, dichloromethane,1,2-dimethoxyethane, 1,4-dioxane, water, and mixed solvents thereof. Thereaction temperature is preferably 0° C. to 120° C.

In the above formulae, Ar^(1w) represents an aromatic hydrocarbon cyclicgroup having six to fourteen carbon atoms which may be substituted or a5 to 14-membered aromatic heterocyclic group which may be substituted;R^(2w) and R^(3w) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted; R^(4w) represents a hydrogen atom, ahalogen atom, a cyano group, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, an aromatic hydrocarboncyclic group having six to fourteen carbon atoms which may besubstituted, a 5 to 14-membered aromatic heterocyclic group which may besubstituted, a nitrogen atom which may be substituted, an oxygen atomwhich may be substituted or a sulfur atom which may be substituted; thering A^(w) represents a pyridyl group, a pyrimidinyl group, a pyrazinylgroup or a pyridazinyl group; the ring A′^(w) represents adihydrooxopyridinyl group, a dihydrooxopyrimidinyl group, adihydrooxopyrazinyl group or a dihydrooxopyridazinyl group; and X^(w)represents a halogen atom. The compound (W2) of the present inventioncan be produced, for example, by this Production Process W. That is, thecompound (W2) can be produced by hydrolyzing the compound (W1) as astarting material under acidic conditions. The acid used variesdepending on the starting materials, reagents, solvent, and so on used.Preferably, although not specifically limited to as far as the reactionis not inhibited, the acid is hydrochloric acid, hydrobromic acid,sulfuric acid, or the like. This reaction is preferably carried out inwater, or alternatively carried out in a mixed solvent of water withacetic acid or alcohols such as ethanol, for instance. Furthermore, thereaction temperature is generally room temperature to about 120° C.,preferably 80° C. to 100° C.

In the above formulae, Ar^(1x) represents an aromatic hydrocarbon cyclicgroup having six to fourteen carbon atoms which may be substituted or a5 to 14-membered aromatic heterocyclic group which may be substituted;R^(2x) and R^(3x) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted, a 5 to 14-membered aromatic heterocyclic groupwhich may be substituted, an acyl group having one to six carbon atomswhich may be substituted or an alkylsulfonyl group having one to sixcarbon atoms which may be substituted; R^(4x) represents a hydrogenatom, a halogen atom, a cyano group, an alkyl group having one to sixcarbon atoms which may be substituted, an alkenyl group having two tosix carbon atoms which may be substituted, an alkynyl group having twoto six carbon atoms which may be substituted, an aromatic hydrocarboncyclic group having six to fourteen carbon atoms which may besubstituted, a 5 to 14-membered aromatic heterocyclic group which may besubstituted, a nitrogen atom which may be substituted, an oxygen atomwhich may be substituted or a sulfur atom which may be substituted;R^(9x) and R^(10x) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted; the ring A^(x) represents a pyridylgroup, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, adihydrooxopyridinyl group, a dihydrooxopyrimidinyl group, adihydrooxopyrazinyl group or a dihydrooxopyridazinyl group; and B^(x)represents an alkyl group having one to six carbon atoms which may besubstituted, an alkenyl group having two to six carbon atoms which maybe substituted, an alkynyl group having two to six carbon atoms whichmay be substituted, a cycloalkyl group having three to eight carbonatoms which may be substituted, a cycloalkenyl group having three toeight carbon atoms which may be substituted, a 5 to 14-memberednon-aromatic heterocyclic group which may be substituted, an aromatichydrocarbon cyclic group having six to fourteen carbon atoms which maybe substituted or a 5 to 14-membered aromatic heterocyclic group whichmay be substituted. The compound (X2) of the present invention can beproduced by dehydration-condensation of a carboxylic acid derivative(X1) with amine in the presence of a condensing agent in a solvent. Thecondensing agent used is preferably3-(3′-dimethylaminopropyl)-1-ethylcarbodiimide. The reaction can beaccelerated by the addition of 1-hydroxybenzotriazole or the like.Furthermore, when the amine to be condensed with the carboxylic acidforms a salt with hydrogenchloride or the like, an appropriate amount oftertiary amine such as triethylamine is added. Preferable examples ofthe solvent used include ethers such as tetrahydrofuran, dioxane,1,2-dimethoxyethane or diethylene glycol, N,N-dimethylformamide and1-methylpyrrolidinone. The reaction temperature is generally 0° C. to50° C., preferably around room temperature.

In the above formulae, R^(1y) represents an aromatic hydrocarbon cyclicgroup having six to fourteen carbon atoms which may be substituted or a5 to 14-membered aromatic heterocyclic group which may be substituted;R^(2y) represents a hydrogen atom or an alkyl group having one to sixcarbon atoms; R^(3y) represents an alkyl group having one to six carbonatoms which may be substituted, an aromatic hydrocarbon cyclic grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted; andX^(y) represents a halogen atom. The compound (Y4) as a raw material forthe production of the compound represented by the formula (I) of thepresent invention can be produced by this Production Process Y.Step Y-1: This step is to produce the compound (Y2) by allowing areducing agent to react with the compound (Y1) in a solvent to convertthe ester or carboxyl group of the compound (Y1) into a hydroxymethylgroup. The reducing agent used is preferably sodium tetrahydroborate,lithium aluminum hydride, a borane-tetrahydrofuran complex, or the like.The solvent used varies depending on the starting materials, reagents,and so on. Preferably, although not specifically limited to insofar asthe reaction is not inhibited and the starting materials are dissolvedto a certain degree, the solvents include alcohols such as ethanol andethers such as diethyl ether, tetrahydrofuran, and 1,4-dioxane. Thereaction temperature is preferably −20° C. to room temperature.Step Y-2: This step is to produce the sulfonic acid ester derivative(Y4) by allowing the compound (Y2) to react with the sulfonyl halidederivative (Y3) in a solvent in the presence of a base. The base used inthe reaction is preferably tertiary amine such as triethylamine. Thesolvent used varies depending on the starting materials, reagents, andso on. Preferably, although not specifically limited to insofar as thereaction is not inhibited and the starting materials are dissolved to acertain degree, the solvents include dichloromethane, dichloroethane,diethyl ether, tetrahydrofuran, and 1,4-dioxane. The reactiontemperature is preferably −20° C. to room temperature.

In the above formulae, Ar^(1z) represents an aromatic hydrocarbon cyclicgroup having six to fourteen carbon atoms which may be substituted or a5 to 14-membered aromatic heterocyclic group which may be substituted;R^(2z) and R^(3z) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted, a 5 to 14-membered aromatic heterocyclic groupwhich may be substituted, an acyl group having one to six carbon atomswhich may be substituted or an alkylsulfonyl group having one to sixcarbon atoms which may be substituted; R^(4z) represents a hydrogenatom, a cyano group, an alkyl group having one to six carbon atoms whichmay be substituted, an alkenyl group having two to six carbon atomswhich may be substituted, an alkynyl group having two to six carbonatoms which may be substituted, an aromatic hydrocarbon cyclic grouphaving six to fourteen carbon atoms which may be substituted, a 5 to14-membered aromatic heterocyclic group which may be substituted, anitrogen atom which may be substituted, an oxygen atom which may besubstituted or a sulfur atom which may be substituted; the ring A^(z)represents a pyridyl group, a pyrimidinyl group, a pyrazinyl group or apyridazinyl group; and X^(z) represents a halogen atom. The compound(Z2) of the present invention can be produced by the reaction of thecompound (Z1) and alkali metal cyanide in a solvent. The alkali metalcyanide used in the reaction is preferably sodium cyanide or potassiumcyanide. The solvent used varies depending on the starting materials,regents, and so on. Preferably, although not specifically limited toinsofar as the reaction is not inhibited and the starting materials aredissolved to a certain degree, the solvents include dimethylsulfoxide,N,N-dimethylformamide and N-methylpyrrolidone. The reaction temperatureis preferably 100° C. to 200° C.

Typical examples of the production processes for the compounds (I)according to the present invention have been illustrated above. Thematerial compounds used in the production of the compounds of thepresent invention may form salts and/or solvates and are notspecifically limited, as long as they do not adversely affect thereaction. When the compounds (I) according to the present invention areobtained as free form, they can be converted into possible salts of theabove-mentioned compounds (I) according to a conventional procedure.Various isomers such as geometrical isomers, optical isomers based on anasymmetric carbon, rotational isomers, stereoisomers, and tautomersobtained as the compounds (I) according to the present invention can bepurified and isolated according to a conventional separation means. Suchseparation means include, for example, recrystallization, diastereomericsalt method, enzymatic resolution, and a variety of chromatography suchas thin layer chromatography, column chromatography or gaschromatography.

The compounds represented by the formula (I) according to the presentinvention, salts thereof or solvates of them can be formulated intopharmaceutical preparations as intact or as a mixture with, for example,a known pharmacologically acceptable carrier according to a conventionalprocedure. Preferred dosage forms are tablets, powders, subtle granules,granules, coated tablets, capsules, syrups, troches, inhalants,suppositories, injections, ointments, ophthalmic ointments, eye drops,nasal drops, ear drops, cataplasms, and lotions. In the formulation,generally used fillers, binders, disintegrators, lubricants, coloringagents, and flavoring agents, as well as stabilizers, emulsifiers,absorbefacients, surfactants, pH adjusting agents, antiseptics, andantioxidants according to necessity can be used. They can be formulatedaccording to a conventional procedure using components generally used asraw materials for pharmaceutical preparations. Examples of suchcomponents include (1) animal and vegetable oils such as soybean oil,beef tallow and synthetic glycerides; (2) hydrocarbons such as liquidparaffins, squalane and solid paraffins; (3) ester oils such asoctyldodecyl myristate and isopropyl myristate; (4) higher alcohols suchas cetostearyl alcohol and behenyl alcohol; (5) silicone resins; (6)silicone oils; (7) surfactants such as polyoxyethylene fatty acidesters, sorbitan fatty acid esters, glycerin fatty acid esters,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenatedcastor oils and polyoxyethylene-polyoxypropylene block copolymers; (8)water-soluble polymers such as hydroxyethyl cellulose, poly(acrylicacid)s, carboxyvinyl polymers, polyethylene glycol, polyvinylpyrrolidoneand methylcellulose; (9) lower alcohols such as ethanol and isopropanol;(10) polyhydric alcohols such as glycerol, propylene glycol, dipropyleneglycol and sorbitol; (11) sugars such as glucose and sucrose; (12)inorganic powders such as silicic anhydride, magnesium aluminiumsilicate and aluminium silicate; and (13) purified water. 1) The fillersinclude, for example, lactose, corn starch, sucrose, glucose, mannitol,sorbitol, crystalline cellulose and silicon dioxide; 2) the bindersinclude, for example, polyvinyl alcohol, polyvinyl ether,methylcellulose, ethylcellulose, gum arabic, gum tragacanth, gelatin,shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene blockpolymers, meglumine, calcium citrate, dextrin and pectin; 3) thedisintegrators include, for example, starch, agar, gelatin powder,crystalline cellulose, calcium carbonate, sodium hydrogencarbonate,calcium citrate, dextrin, pectin and carboxymethylcellulose calcium; 4)the lubricants include, for example, magnesium stearate, talc,polyethylene glycol, silica, and hardened vegetable oils; 5) thecoloring agents can be any coloring agents which are approved to add topharmaceutical preparations; 6) the flavoring agents include, forexample, cocoa powder, menthol, aromatic powder (empasm), peppermintoil, camphol (borneol) and cinnamon powder; and 7) the antioxidants canbe any antioxidants which are approved to add to pharmaceuticalpreparations, such as ascorbic acid and α-tocopherol.

1) The oral preparation is produced by mixing the compound according tothe present invention or a salt thereof with a filler, and if necessary,a binder, disintegrator, lubricant, coloring agent, flavoring agent, andother components, and formulating the mixture according to aconventional procedure into, for example, a powder, subtle granules,granules, tablet, coated tablet or capsules. 2) The tablets and granulescan be appropriately coated with, for example, sugar or gelatinaccording to necessity. 3) The liquid formulations such as syrups,injection preparations or eye drops can be prepared according to aconventional procedure by adding a pH adjusting agent, solubilizer, andisotonizing agent, and if necessary, a solubilizing agent, stabilizer,buffer, suspending agent, antioxidant, and other components. The liquidformulations can also be formed into freeze-dried products. Theinjections can be administered intravenously, subcutaneously and/orintramuscularly. Preferred examples of the suspending agents aremethylcellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic,powdered tragacanth, carboxymethylcellulose sodium and polyoxyethylenesorbitan monolaurate; preferred examples of the solubilizers arepolyoxyethylene hydrogenated caster oil, polysorbate 80, nicotinamideand polyoxyethylene sorbitan monolaurate; preferred examples of thestabilizers are sodium sulfite, sodium metasulfite and ether; preferredexamples of the preservatives are methyl p-hydroxybenzoate, ethylp-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol. 4) Theexternal preparations can be produced according to a conventionalprocedure not specifically limited. Base materials for use herein can beany raw materials generally used in, for example, pharmaceuticalpreparations, quasi drugs and cosmetics. Such raw materials include, forexample, animal and vegetable oils, mineral oils, ester oils, waxes,higher alcohols, fatty acids, silicone oils, surfactants, phospholipids,alcohols, polyhydric alcohols, water-soluble polymers, clay minerals,and purified water. Where necessary, any of pH adjusting agents,antioxidants, chelating agents, antiseptics and antimolds, coloringagents, flavors, and others can be added. In addition, components havingdifferentiation-inducing action, blood-flow accelerators, bactericides,anti-inflammatory agents, cell activators, vitamins, amino acids,humectants, keratolytic agents, and other components can be addedaccording to necessity.

The dose of the pharmaceutical preparation according to the presentinvention varies depending on the degree of symptom, age, sex, bodyweight, administration mode, type of the salt, difference in sensibilityto the drug, concrete type of the disease and other factors. Generally,the pharmaceutical preparation may be administered to an adult in one toseveral divided doses at a daily dose of about 30 μg to about 10 g,preferably 100 μg to 5 g, and more preferably 100 μg to 100 mg for oraladministration, or about 30 μg to about 1 g, preferably 100 μg to 500mg, and more preferably 100 μg to 30 mg for injection administration.

The present invention can provide a novel pyrimidine compound. Thecompounds according to the present invention, salts thereof or solvatesof them have an excellent antagonism against an adenosine receptor(adenosine A₁, A_(2A), A_(2B) or A₃ receptor) and are specificallyexcellent as an antagonist against the adenosine A₂ receptors,specifically against the adenosine A_(2A) and/or A_(2B) receptor. Theyare useful as an agent for treating or preventing a disease to which theadenosine receptor (adenosine A₁, A_(2A), A_(2B) or A₃ receptor) relatesand a disease against which an antagonist of the receptor isefficacious. They are useful as an agent for treating, preventing orimproving various constipations (functional constipation, irritablebowel syndrome, constipation accompanying irritable bowel syndrome,organic constipation, constipation accompanying enteroparalytic ileus,constipation accompanying congenital digestive tract dysfunction,constipation accompanying ileus), as an agent for treating, preventingor improving diabetes mellitus, diabetic complications, diabeticretinopathy, obesity or asthma, and are also useful as, for example, ahypoglycemic agent, agent for ameliorating glucose intolerance, insulinsensitizer, antihypertensive drug, diuretic agent, antidepressant, agentfor treating osteoporosis, agent for treating Parkinson's disease, agentfor treating Alzheimer's disease, agent for treating an inflammatorybowel disease or agent for treating Crohn's disease.

EXAMPLES

The following Reference Examples, Examples and Test Examples areillustrative, and the compounds of the present invention are under nocircumstances restricted by the following examples. Those skilled in theart can modify not only the following Examples but also the claimsaccording to the present description in various ways to exploit to thefull of the present invention, and such modifications and variations arealso included within the scope of the appended claims relating to thepresent description.

Reference Example 1 Ethyl(E)-3-(3-fluorophenyl)-2-(4-pyridyl)-2-propenoate

A solution of ethyl 4-pyridylacetate (25.0 g, 0.151 mol) and3-fluorobenzaldehyde (20.7 g, 0.167 mol) in a mixture of aceticanhydride (100 mL) and triethylamine (20 mL) was heated under reflux for5.5 hours. After standing to cool, the reaction mixture wasconcentrated. The residue was diluted with ethyl acetate and a saturatedaqueous sodium hydrogencarbonate solution, and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith a saturated aqueous sodium hydrogencarbonate solution twice andbrine, dried over anhydrous sodium sulfate and then concentrated. Theresidue was subjected to silica gel column chromatography (eluent;hexane, hexane:ethyl acetate=9:1), to give the title compound (25.5 g,62%) as a red-orange oil.

¹H NMR (400 MHz, CDCl₃) δ ppm; 1.28 (3H, t, J=7.2 Hz), 4.27 (2H, q,J=7.2 Hz), 6.70-6.75 (1H, m), 6.80-6.84 (1H, m), 6.91-6.97 (1H, m),7.12-7.18 (1H, m), 7.16 (2H, dd, J=1.6, 4.4 Hz), 7.85 (1H, s), 8.62 (2H,dd, J=1.6, 4.4 Hz).

Reference Example 2 Ethyl (E)-3-(2-furyl)-2-(4-pyridyl)-2-propenoate

The title compound was synthesized in a similar manner to ReferenceExample 1 using 2-furaldehyde.

¹H NMR (400 MHz, CDCl₃) δ ppm; 1.20 (3H, t, J=7.2 Hz), 4.18 (2H, q,J=7.2 Hz), 6.51 (1H, d, J=3.6 Hz), 6.54 (1H, dd, J=1.6, 3.6 Hz), 7.29(2H, dd, J=1.6, 4.4 Hz), 7.66 (1H, s), 7.69 (1H, d, J=1.6 Hz), 8.62 (2H,dd, J=1.6, 4.4 Hz).

Reference Example 3 (E)-4-(2-Furyl)-3-(4-pyridyl)-3-buten-2-one

Under a nitrogen atmosphere, a 3.0M solution of methylmagnesium bromidein diethyl ether (3.7 ml, 11.1 mmol) was added dropwise over 5 minutesto a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran(22 ml, 22 mmol) at −50° C. (dry ice-acetone bath), followed by stirringas it was for 1 hour. Then, a solution of ethyl(E)-3-(2-furyl)-2-(4-pyridyl)-2-propenoate (2.4 g, 9.87 mmol) intetrahydrofuran (20 ml) was added dropwise thereinto over 5 minutes. Thereaction mixture was stirred for 30 minutes while elevating to roomtemperature, and then the reaction was terminated by adding hydrochloricacid. After diluting with a saturated aqueous ammonium chloridesolution, the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate andconcentrated. The residue was subjected to silica gel columnchromatography (elution solvent; hexane:ethyl acetate=1:1 to 4:1), togive the title compound (0.52 g, 23%).

¹H NMR (400 MHz, CDCl₃) δ ppm; 2.36 (3H, s), 6.07 (1H, d, J=3.2 Hz),6.34 (1H, dd, J=1.6, 3.2 Hz), 7.16 (2H, dd, J=1.8, 4.4 Hz), 7.38 (1H, d,J=1.6 Hz), 7.55 (1H, s), 8.70 (2H, dd, J=1.8, 4.4 Hz).

Reference Example 4(E)-3-(3-Fluorophenyl)-2-(4-pyridyl)-2-propenenitrile

Sodium (3.0 g, 130 mmol) was dissolved in ethanol (150 mL),4-pyridylacetonitrile hydrochloride (10 g, 65 mmol) was added thereto,and then the mixture was stirred at room temperature. After 10 minutes,3-fluorobenzaldehyde (8 g, 65 mmol) was added thereto, followed bystirring as it was for 30 minutes. The resulting precipitates werecollected by filtration and washed with a small portion of water, togive the title compound (8.2 g, 56%) as a colorless solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 7.40-7.46 (1H, m), 7.61-7.68 (1H, m),7.75 (2H, dd, J=1.6, 4.4 Hz), 7.77-7.86 (2H, m), 8.37 (1H, s), 8.73 (2H,dd, J=1.6, 4.4 Hz).

Reference Example 5 1-(2-Furyl)-2-(4-pyridyl)-1-ethanone

To a solution of 4-picoline (4.6 g, 49.4 mmol) and ethyl2-furancarboxylate (7.7 g, 54.9 mmol) in tetrahydrofuran (40 ml) wasdropwise added lithium bis(trimethylsilyl)amide (100 ml, 100 mmol) over1 hour at 0° C. under an atmosphere of nitrogen gas, followed bystirring as it was for 2 hours. Hexane (140 ml) was added to thereaction mixture, and the resulting crystals were collected byfiltration. The resulting crystals were dissolved in ethyl acetate and asaturated aqueous ammonium chloride solution. The organic layer waswashed with a saturated aqueous ammonium chloride solution twice andbrine, dried over anhydrous sodium sulfate and concentrated. Hexane wasadded to the residue, and the resulting precipitates were collected byfiltration and washed with hexane, to give the title compound (6.5 g,70%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.26 (2H, s), 6.77 (1H, dd, J=2.0, 3.6Hz), 7.31 (2H, dd, J=1.6, 4.4 Hz), 7.65 (1H, dd, J=0.8, 3.6 Hz), 8.05(1H, dd, J=0.8, 2.0 Hz), 8.51 (2H, dd, J=1.6, 4.4 Hz).

Reference Example 63-(Dimethylamino)-1-(2-furyl)-2-(4-pyridyl)-2-propen-1-one

N,N-Dimethylformamide dimethyl acetal (5 ml) was added to1-(2-furyl)-2-(4-pyridyl)-1-ethanone (2.0 g, 10.7 mmol) and the mixturewas stirred at 100° C. for 2 hours. After cooling as it was, thereaction mixture was diluted with ethyl acetate and a saturated aqueousammonium chloride solution. The aqueous layer was extracted with ethylacetate (×6). The combined organic layers were dried over anhydroussodium sulfate and then concentrated, to give the title compound (2.5 g,97%) as a reddish brown oil.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.80 (6H, br s), 6.53 (1H, br), 6.60(1H, br), 7.10 (2H, d, J=4.0 Hz), 7.65 (1H, br), 7.75 (1H, s), 8.44 (2H,d, J=4.0 Hz).

Reference Example 7 (6-Chloro-3-pyridyl)methanol

To a solution of ethyl 6-chloronicotinate (25.8 g, 0.139 mol) in ethanolwas added sodiumborohydride (10.5 g, 0.278 mol), followed by stirringunder an atmosphere of nitrogen gas at room temperature. After 41 hours,the reaction mixture was concentrated and then the residue was dilutedwith a saturated aqueous ammonium chloride solution and ethyl acetate.The organic layer was washed with a saturated aqueous ammonium chloridesolution, dried over anhydrous sodium sulfate and concentrated. Theresidue was subjected to silica gel column chromatography (elutionsolvent; hexane, hexane:ethyl acetate=4:1, 2:1, and 3:2), to give thetitle compound (11.7 g, 58%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.54 (2H, d, J=5.6 Hz), 5.43 (1H, t,J=5.6 Hz), 7.48 (1H, d, J=8.4 Hz), 7.80 (1H, dd, J=2.4, 8.4 Hz), 8.35(1H, d, J=2.4 Hz).

Reference Example 8 (6-Chloro-3-pyridyl)methyl methanesulfonate

To a solution of (6-chloro-3-pyridyl)methanol (4.5 g, 31.3 mmol) andtriethylamine (13.2 ml, 94.7 mmol) in dichloromethane (90 ml) wasdropwise added methanesulfonyl chloride (3.6 ml, 46.5 mmol) over 45minutes at −9° C. to 4° C. under an atmosphere of nitrogen gas, followedby stirring as it was. After 1 hour, the reaction mixture was elevatedto room temperature. The reaction mixture was washed with an aqueoussaturated sodium bicarbonate solution and a saturated aqueous ammoniumchloride solution, dried over anhydrous sodium sulfate and concentrated,to give the title compound (6.14 g, 88%) as a pale brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.30 (3H, s), 5.34 (2H, s), 7.61 (1H,dd, J=0.6, 8.0 Hz), 7.97 (1H, dd, J=2.4, 8.0 Hz), 8.53 (1H, dd, J=0.6,2.4 Hz).

Reference Example 9 2-(6-Chloro-3-pyridyl)-1-(2-furyl)-1-ethanone

To a mixture of 2-furaldehyde (7.9 g, 82.2 mmol) and zinc (II) iodide(110 mg, 0.345 mmol) was dropwise added trimethylsilyl cyanide (11.0 ml,82.5 mmol) over 10 minutes at 0° C. under an atmosphere of nitrogen gas,followed by stirring as it was. After 30 minutes, the reaction mixturewas diluted with tetrahydrofuran (200 ml) and then cooled to −78° C. A1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (86ml, 86 mmol) was added dropwise thereto over 1 hour and then a solutionof (6-chloro-3-pyridyl)methyl methanesulfonate (18.1 g, 81.7 mmol) intetrahydrofuran (50 ml) was added dropwise over 1.5 hours thereto,followed by stirring while gradually elevated to room temperature. After12.5 hours, a 1.0M solution of tetrabutylammonium fluoride intetrahydrofuran (86 ml, 86 mmol) was added thereto, followed by stirringas it was. After further 30 minutes, the reaction mixture was dilutedwith a saturated aqueous ammonium chloride solution and ethyl acetate.The resulting organic layer was washed with a saturated aqueous ammoniumchloride solution twice, dried over anhydrous sodium sulfate andconcentrated. The residue was subjected to silica gel columnchromatography (elution solvent; hexane, hexane:ethyl acetate=10:1, 4:1,3:1, and 2:1) and then suspended in hexane. Subsequently, the resultingprecipitates were collected by filtration, to give the title compound(11.9 g, 54%) as a pale brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.31 (2H, s), 6.78 (1H, dd, J=1.8, 3.4Hz), 7.50 (1H, d, J=8.4 Hz), 7.64 (1H, d, J=3.4 Hz), 7.77 (1H, dd,J=2.4, 8.4 Hz), 8.06 (1H, d, J=1.8 Hz), 8.33 (1H, d, J=2.4 Hz).

Reference Example 102-(6-Chloro-3-pyridyl)-3-(dimethylamino)-1-(2-furyl)-2-propen-1-one

The title compound was synthesized in a similar manner to ReferenceExample 6 using 2-(6-chloro-3-pyridyl)-1-(2-furyl)-1-ethanone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.79 (6H, br s), 6.55 (1H, dd, J=2.0,3.4 Hz), 6.62 (1H, d, J=3.4 Hz), 7.45 (1H, d, J=8.0 Hz), 7.59 (1H, dd,J=2.4, 8.0 Hz), 7.77 (2H, d, J=2.0 Hz), 8.14 (1H, d, J=2.4 Hz).

Reference Example 11(E)-3-(3-Fluorophenyl)-2-(6-methoxy-3-pyridyl)-2-propenenitrile

To a suspension of sodium hydride (8.8 g, 0.220 mol) in1,2-dimethoxyethane (300 ml) was added diethyl cyanomethylphosphonate(19.7 g, 0.122 mol) little by little at room temperature under anatmosphere of nitrogen gas. After stirring for 15 minutes,5-bromo-2-methoxypyridine (20.0 g, 0.106 mol) andtetrakis(triphenylphosphine)palladium (0) (2.0 g, 1.73 mmol) weresuccessively added thereto, followed by heating to 90° C. and stirringfor 6 hours. The reaction mixture was cooled as it was and furtherice-cooled. 3-Fluorobenzaldehyde (13.7 g, 0.110 mol) was added dropwisethereto over 1.5 hours at 1 to 4° C. under an atmosphere of nitrogengas, followed by stirring further for 2.5 hours while graduallyelevating to room temperature. The reaction mixture was diluted with asaturated aqueous ammonium chloride solution and ethyl acetate, and thenthe aqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with a saturated aqueous ammonium chloride solutiontwice, dried over anhydrous sodium sulfate and then concentrated. Theresidue was suspended in methanol, and then the resulting solid wascollected by filtration and washed with diethyl ether and hexane, togive the title compound (7.80 g, 29%) as a colorless solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.92 (3H, s), 7.00 (1H, d, J=8.8 Hz),7.34-7.40 (1H, m), 7.57-7.64 (1H, m), 7.69-7.78 (2H, m), 8.03 (1H, s),8.11 (1H, dd, J=2.6, 8.8 Hz), 8.53 (1H, d, J=2.6 Hz).

Reference Example 122-Amino-6-(3-fluorophenyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone

Sodium (3.2 g, 139 mmol) was dissolved in ethanol (200 ml), and then4-pyridylacetonitrile (10.0 g, 64.7 mmol), 3-fluorobenzaldehyde (7.3 ml,68.8 mmol) and guanidine hydrochloride (7.0 g, 73.3 mmol) weresuccessively added thereto, followed by heating under reflux for 2 days.The insoluble matters were filtered off and the filtrate wasconcentrated. The residue was subjected to silica gel columnchromatography (elution solvent; dichloromethane,dichloromethane:methanol=20:1, 10:1, 5:1), to give a 5,6-dihydro product(13.6 g) of the title compound as a crude product. Sulfur (26.4 g, 82.3mmol as S) was added to the product, followed by heating at 185° C. for2.5 hours. After cooling as it was, the reaction mixture was suspendedin methanol, and the insoluble matters were filtered off and washed with2N hydrochloride. Methanol in the filtrate was concentrated and theresidue was washed with ethyl acetate twice. The aqueous layer wasadjusted to pH 11 with a 5N aqueous sodium hydroxide solution, washedwith ethyl acetate twice and then neutralized with 2N hydrochloride. Theresulting crystals were collected by filtration, and washed with waterand ethyl acetate, to give the title compound (6.2 g, 34%) as acolorless solid. Furthermore, in this method, the title compound wasalso obtained by isolating(E)-3-(3-fluorophenyl)-2-(4-pyridyl)-2-propenenitrile and thensubjecting it to a cyclization reaction with guanidine in a similarmanner to Reference Example 4.

(Method 2)

Sodium (3.4 g, 147 mmol) was dissolved in ethanol (500 ml), and thenethyl (E)-3-(3-fluorophenyl)-2-(4-pyridyl)-2-propenoate (33 g, 121 mmol)and guanidine hydrochloride (13.9 g, 146 mmol) were added thereto,followed by heating under reflux for 13 hours. After cooling as it was,the solvent was removed. Tetrahydrofuran (500 ml) was added to theresidue, the insoluble matters were filtered off, and the filtrate wasconcentrated. To a solution of the residue in tetrahydrofuran (1500ml)-methanol (100 ml) was added active manganese dioxide (250 g),followed by heating under reflux. After 2 hours, additional activemanganese dioxide (100 g) was added thereto, followed by heating underreflux further for 1 hour and 15 minutes. After cooling as it was, themanganese dioxide was filtered off through Celite and washed withtetrahydrofuran and methanol. The collected filtrate was concentratedand acetonitrile was added to the residue. The resulting precipitateswere collected by filtration, to give the title compound (15 g, 44%) asa yellow powder.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.86 (2H, br s), 6.96 (1H, d, J=7.6Hz), 7.00-7.07 (3H, m), 7.00-7.15 (1H, m), 7.20-7.28 (1H, m), 8.34 (2H,d, J=3.2 Hz); MS m/e (ESI) 283 (MH⁺).

Reference Example 132-Amino-6-(2-furyl)-5-(4-pirydyl)-3,4-dihydro-4-pyrimidinone

The title compound was synthesized in a similar manner to Method 1 ofReference Example 12 using 2-furaldehyde.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.48 (1H, dd, J=1.6, 3.6 Hz), 6.54 (1H,dd, J=0.8, 3.6 Hz), 6.91 (2H, br s), 7.21 (2H, dd, J=1.6, 4.6 Hz), 7.54(1H, dd, J=0.8, 1.6 Hz), 8.52 (2H, dd, J=1.6, 4.6 Hz); MS m/e (ESI) 255(MH⁺).

Reference Example 14 3-(Dimethylamino)-1-(2-furyl)-2-propen-1-one

A mixture of 2-acetylfuran (25.0 g, 0.227 mol) and N,N-dimethylformamidedimethylacetal (40 ml) was stirred at 100° C. for 9 hours. After coolingas it was, the reaction mixture was concentrated. To the residue wereadded diethyl ether and hexane. The resulting solid was collected byfiltration and washed with hexane, to give the title compound (36.5 g,97%) as a brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.88 (3H, br s), 3.14 (3H, br s), 5.65(1H, d, J=12.6 Hz), 6.60 (1H, dd, J=2.0, 3.4 Hz), 7.10 (1H, dd, J=0.8,3.4 Hz), 7.68 (1H, d, J=12.6 Hz), 7.79 (1H, dd, J=0.8, 2.0 Hz).

Reference Example 15 4-(2-Furyl)-2-pyrimidinylamine

A suspension of 3-(dimethylamino)-1-(2-furyl)-2-propen-1-one (5.0 g,30.3 mmol), guanidine hydrochloride (5.8 g, 60.7 mmol) and potassiumcarbonate (8.4 g, 60.9 mmol) in N,N-dimethylformamide (50 ml) wasstirred at 100° C. for 21 hours. After cooling as it was, the reactionmixture was diluted with ice water (250 ml). The resulting solid wascollected by filtration and washed with water, to give the titlecompound (4.19 g, 86%) as a pale brown solid.

¹H NMR (400 MHz, DMSO-d6) δ ppm; 6.66 (2H, br s), 6.68 (1H, dd, J=2.0,3.2 Hz), 6.88 (1H, d, J=5.2 Hz), 7.17 (1H, dd, J=0.8, 3.2 Hz), 7.88 (1H,dd, J=0.8, 2.0 Hz), 8.28 (1H, d, J=5.2 Hz); MS m/e (ESI) 162 (MH⁺).

Reference Example 16 5-bromo-4-(2-furyl)-2-pyrimidinylamine

To a solution of 4-(2-furyl)-2-pyrimidinylamine (4.10 g, 25.4 mmol) inN,N-dimethylformamide (40 ml) was added N-bromosuccinimide (4.53 g, 25.5mmol) at 2° C., followed by stirring as it was. After 6 hours, thereaction mixture was diluted with an aqueous saturated sodiumbicarbonate solution (240 ml). The mixture was ice-cooled, and then thecrystals were collected by filtration and washed with water, to give thetitle compound (5.10 g, 84%) as a pale brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.73 (1H, dd, J=1.6, 3.6 Hz), 6.96 (2H,br s), 7.50 (1H, dd, J=0.8, 3.6 Hz), 7.97 (1H, dd, J=0.8, 1.6 Hz), 8.41(1H, s).

Reference Example 17 2-(Benzyloxy)-5-bromopyridine

To a solution of benzyl alcohol (11.4 g, 0.105 mol) inN,N-dimethylformamide (250 ml) was added 70% oily sodium hydride (4.2 g,0.123 mol) at 0° C., followed by stirring as it was for 1.5 hours. Then,2,5-dibromopyridine (25 g, 0.106 mol) was added thereto, followed bystirring at 70° C. for 2 hours. After cooling as it was, the reactionmixture was diluted with a saturated aqueous ammonium chloride solutionand extracted with ethyl acetate. The resulting organic layer was washedwith a saturated aqueous ammonium chloride solution twice, dried overanhydrous magnesium sulfate and concentrated, to give a crude product ofthe title compound (29.5 g) as a pale yellow liquid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 5.33 (2H, s), 6.90 (1H, d, J=9.0 Hz),7.30-7.41 (3H, m), 7.41-7.46 (2H, m), 7.92 (1H, dd, J=2.8, 9.0 Hz), 8.30(1H, d, J=2.8 Hz).

Reference Example 18 2-(Benzyloxy)-5-(1,1,1-tributylstanyl)pyridine

To a suspension of the above crude product (29.5 g) of2-(benzyloxy)-5-bromopyridine in diethyl ether (300 ml) was dropwiseadded a 2.66 M solution of n-butyl lithium in hexane (40 ml, 0.106 mol)over 30 minutes at −76° C. to −72° C. under an atmosphere of nitrogengas. Subsequently, tetrahydrofuran (170 ml) was added dropwise thereto,followed by stirring as it was. After 1.5 hours, a solution oftributyltin chloride (35 g, 0.114 mol) in tetrahydrofuran (50 ml) wasadded dropwise thereto over 1.5 hours. Then, the reaction mixture wasstirred as it was while gradually elevating to room temperature. After 6hours, the reaction mixture was diluted with a saturated aqueousammonium chloride solution and ethyl acetate. The resulting organiclayer was washed with a saturated aqueous ammonium chloride solutiontwice, dried over anhydrous sodium sulfate and concentrated. The residuewas subjected to silica gel column chromatography (elution solvent;hexane, hexane:ethyl acetate=20:1), to give the title compound (47.0 g,94%) as a colorless oil.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 0.85 (9H, t, J=7.6 Hz), 0.97-1.15 (6H,m), 1.29 (6H, sex, J=7.6 Hz), 1.46-1.55 (6H, m), 5.33 (2H, s), 6.85-6.90(1H, m), 7.29-7.41 (3H, m), 7.41-7.47 (2H, m), 7.66-7.78 (1H, m),8.08-8.15 (1H, m).

Reference Example 19 2-(2-Fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone

The title compound was synthesized in a similar manner to ReferenceExample 5 using 2-fluoro-4-methylpyridine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.36 (2H, s), 6.76 (1H, dd, J=1.6, 3.6Hz), 7.11 (1H, br), 7.24-7.29 (1H, m), 7.63 (1H, dd, J=0.4, 3.6 Hz),8.05 (1H, dd, J=0.8, 1.6 Hz), 8.17 (1H, d, J=4.8 Hz).

Reference Example 20 2-(2-Bromo-4-pyridyl)-1-(2-furyl)-1-ethanone

The title compound was synthesized in a similar manner to ReferenceExample 5 using 2-bromo-4-methylpyridine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.31 (2H, s), 6.77 (1H, dd, J=1.6, 3.6Hz), 7.36 (1H, dd, J=1.6, 5.2 Hz), 7.60 (1H, dd, J=0.4, 1.6 Hz), 7.62(1H, dd, J=0.8, 3.6 Hz), 8.05 (1H, dd, J=0.8, 1.6 Hz), 8.32 (1H, dd,J=0.4, 5.2 Hz).

Reference Example 21 4,6-Di(2-furyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to ReferenceExample 12 using 2-acetylfuran instead of1-(2-furyl)-2-(4-pyridyl)-1-|ethanone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.69 (2H, dd, J=1.6, 3.6 Hz), 6.76 (2H,br s), 7.21 (1H, s), 7.21 (2H, dd, J=0.8, 3.6 Hz), 7.90 (2H, dd, J=0.8,1.6 Hz).

Reference Example 22 5-Bromo-4,6-di(2-furyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to ReferenceExample 16 using 4,6-di(2-furyl)-2-pyrimidinamine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.72 (2H, dd, J=1.6, 3.6 Hz), 7.01 (2H,br s), 7.47 (2H, dd, J=0.8, 3.6 Hz), 7.95 (2H, dd, J=0.8, 1.6 Hz).

Reference Example 23 Alternative Synthetic Method of Reference Example 92-(6-Chloro-3-pyridyl)-1-(2-furyl)-1-ethanone

The title compound was obtained in a similar manner to Reference Example9 using 2-chloro-5-(chloromethyl)pyridine instead of(6-chloro-3-pyridyl)methyl methanesulfonate.

Reference Example 24 2-(6-Chloro-3-pyridyl)-1-(2-thienyl)-1-ethanone

The title compound was obtained in a similar manner to Reference Example9 using 2-thiophenealdehyde.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.46 (2H, s), 7.31 (1H, dd, J=4.0, 4.8Hz), 7.50 (1H, d, J=8.2 Hz), 7.78 (1H, dd, J=2.4, 8.2 Hz), 8.07 (1H, dd,J=1.2, 4.8 Hz), 8.16 (1H, dd, J=1.2, 4.0 Hz), 8.35 (1H, d, J=2.4 Hz).

Reference Example 252-(6-Chloro-3-pyridyl)-3-(dimethylamino)-1-(2-thienyl)-2-propen-1-one

The title compound was obtained in a similar manner to Reference Example6 using 2-(6-chloro-3-pyridyl)-1-(2-thienyl)-1-ethanone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.79 (6H, br s), 7.06 (1H, dd, J=3.8,5.0 Hz), 7.13 (1H, dd, J=1.0, 3.8 Hz), 7.47 (1H, d, J=8.0 Hz), 7.62 (1H,dd, J=2.4, 8.0 Hz), 7.69 (1H, s), 7.73 (1H, dd, J=1.0, 5.0 Hz), 8.16(1H, d, J=2.4 Hz).

Reference Example 26 2-(6-Chloro-3-pyridyl)-1-phenyl-1-ethanone

The title compound was obtained in a similar manner to Reference Example9 using benzaldehyde.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.54 (2H, s), 7.50 (1H, d, J=8.0 Hz),7.55-7.61 (2H, m), 7.66-7.72 (1H, m), 7.76 (1H, dd, J=2.4, 8.0 Hz),8.04-8.09 (2H, m), 8.32 (1H, d, J=2.4 Hz).

Reference Example 272-(6-chloro-3-pyridyl)-3-(dimethylamino)-1-phenyl-2-propen-1-one

The title compound was obtained in a similar manner to Reference Example6 using 2-(6-chloro-3-pyridyl)-1-phenyl-1-ethanone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.73 (6H, br s), 7.29 (1H, s),7.36-7.45 (6H, m), 7.60 (1H, dd, J=2.2, 8.0 Hz), 8.14 (1H, d, J=2.2 Hz).

Reference Example 282-(6-Chloro-3-pyridyl)-1-(3-fluorophenyl)-1-ethanone

The title compound was obtained in a similar manner to Reference Example9 using benzaldehyde.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.55 (2H, s), 7.51 (1H, d, J=8.2 Hz),7.52-7.59 (1H, m), 7.61-7.68 (1H, m), 7.60 (1H, dd, J=2.4, 8.2 Hz),7.82-7.87 (1H, m), 7.90-7.95 (1H, m), 8.31 (1H, d, J=2.4 Hz).

Reference Example 292-(6-Chloro-3-pyridyl)-3-(dimethylamino)-1-(3-fluorophenyl)-2-propen-1-one

The title compound was obtained in a similar manner to Reference Example6 using 2-(6-chloro-3-pyridyl)-1-(3-fluorophenyl)-1-ethanone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.74 (6H, br s), 7.17-7.29 (3H, m),7.31 (1H, s), 7.39-7.47 (2H, m), 7.61 (1H, dd, J=2.2, 8.0 Hz), 8.15 (1H,d, J=2.2 Hz).

Example 1 4-Chloro-6-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinylamine

A suspension of2-amino-6-(3-fluorophenyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone (1.0g, 3.54 mmol) in phosphorus oxychloride (15 ml) was stirred at 100° C.for 30 minutes under an atmosphere of nitrogen gas. After cooling as itwas, the reaction mixture was concentrated and the residue was dissolvedin ethyl acetate and 2N sodium hydroxide. The organic layer was washedwith an aqueous saturated sodium bicarbonate solution twice and brine,dried over anhydrous sodium sulfate and concentrated. To the residue wasadded diethyl ether, and the resulting precipitates were collected byfiltration and washed with diethyl ether, to give the title compound(513 mg, 48%) as a colorless solid.

¹NMR (400 MHz, DMSO-d₆) δ ppm; 7.00-7.03 (1H, m), 7.05-7.10 (1H, m),7.12-7.18 (1H, m), 7.24-7.31 (1H, m), 7.25 (2H, dd, J =1.6, 4.4 Hz),8.51 (2H, dd, J=1.6, 4.4 Hz); MS m/e (ESI) 301 (MH⁻).

Example 2 4-Chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in a similar manner to Example 1using 2-amino-6-(2-furyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinon e.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.27 (1H, d, J=3.6 Hz), 6.48 (1H, dd,J=2.0, 3.6 Hz), 7.34 (2H, dd, J=1.6, 4.4 Hz), 7.35 (2H, br s), 7.67 (1H,dd, J=0.8, 2.0 Hz), 8.66 (2H, dd, J=1.6, 4.4 Hz); MS m/e (ESI) 273(MH⁺).

Example 3 4-(3-Fluorophenyl)-6-methoxy-5-(4-pyridyl)-2-pyrimidinylamine

After sodium (20 mg, 0.870 mmol) was dissolved in methanol (3 ml),4-chloro-6-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinylamine (50 mg,0.166 mmol) was added thereto and the mixture was stirred under anatmosphere of nitrogen gas at 60 to 65° C. for 30 minutes. After coolingas it was, the reaction mixture was diluted with ethyl acetate. Then,the mixture was washed with an aqueous ammonium chloride solution thriceand brine, dried over anhydrous sodium sulfate and concentrated. To theresidue was added diethyl ether, and the resulting precipitates werecollected by filtration and washed with diethyl ether, to give the titlecompound (16 mg, 32%) as a colorless solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.83 (3H, s), 6.90-7.16 (7H, m),7.22-7.29 (1H, m), 8.40 (2H, d, J=4.8 Hz); MS m/e (ESI) 297 (MH⁺).

Example 4 4-Ethoxy-6-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in a similar manner to Example 3using ethanol.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.23 (3H, t, J=7.2 Hz), 4.33 (2H, q,J=7.2 Hz), 6.92 (2H, br s), 6.94-7.16 (5H, m), 7.22-7.29 (1H, m), 8.39(2H, d, J=6.0 Hz); MS m/e (ESI) 311 (MH⁺).

Example 5 4-(3-Fluorophenyl)-6-propoxy-5-(4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in a similar manner to Example 3using 1-propanol.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 0.86 (3H, t, J=7.2 Hz), 1.62 (2H, sex,J=7.2 Hz), 4.22 (2H, t, J=7.2 Hz), 6.92 (2H, br s), 6.96-7.00 (1H, m),7.02-7.16 (2H, m), 7.08 (2H, dd, J=1.6, 4.4 Hz), 7.23-7.29 (1H, m), 8.40(2H, dd, J=1.6, 4.4 Hz); MS m/e (ESI) 325 (MH⁺).

Example 64-(3-Fluorophenyl)-6-isopropoxy-5-(4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in a similar manner to Example 3using 2-propanol.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.23 (6H, d, J=6.0 Hz), 5.32 (1H, m),6.89 (2H, br s), 6.92-7.16 (5H, m), 7.21-7.28 (1H, m), 8.38 (2H, br); MSm/e (ESI) 325 (MH⁺).

Example 7 4-Ethoxy-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in a similar manner to Example 3using 4-chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine and ethanol.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.17 (3H, t, J=6.8 Hz), 4.28 (2H, q,J=6.8 Hz), 6.36 (1H, dd, J=0.8, 3.6 Hz), 6.45 (1H, dd, J=1.6, 3.6 Hz),6.81 (2H, br s), 7.19 (2H, d, J=4.4 Hz), 7.57 (1H, dd, J=0.8, 1.6 Hz),8.54 (2H, d, J=4.4 Hz); MS m/e (ESI) 283 (MH⁺).

Example 8 4-(2-Furyl)-6-propoxy-5-(4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in a similar manner to Example 3using 4-chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine and1-propanol.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 0.80 (3H, t, J=7.2 Hz), 1.56 (2H, sex,J=7.2 Hz), 4.17 (2H, t, J=7.2 Hz), 6.38 (1H, dd, J=0.8, 3.6 Hz), 6.45(1H, dd, J=1.6, 3.6 Hz), 6.80 (2H, br s), 7.19 (2H, dd, J=1.6, 4.4 Hz),7.57 (1H, dd, J=0.8, 1.6 Hz), 8.54 (2H, dd, J=1.6, 4.4 Hz); MS m/e (ESI)297 (MH⁺).

Example 9 4-(2-Furyl)-6-isopropoxy-5-(4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in a similar manner to Example 3using 4-chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine and2-propanol.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.17 (6H, d, J=6.4 Hz), 5.28 (1H, sept,J=6.4 Hz), 6.35 (1H, dd, J=0.8, 3.6 Hz), 6.45 (1H, dd, J=1.6, 3.6 Hz),6.78 (2H, br s), 7.17 (2H, dd, J=1.6, 4.4 Hz), 7.56 (1H, dd, J=0.8, 1.6Hz), 8.53 (2H, dd, J=1.6, 4.4 Hz); MS m/e (ESI) 297 (MH⁺).

Example 10 4-(Allyloxy)-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in a similar manner to Example 3using 4-chloro-6-(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine and allylalcohol.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.77 (2H, dt, J=1.6, 5.2 Hz), 5.12 (1H,dq, J=1.6, 10.4 Hz), 5.14 (1H, dq, J=1.6, 17.2 Hz), 5.93 (1H, ddt,J=5.2, 10.4, 17.2 Hz), 6.38 (1H, dd, J=0.8, 3.4 Hz), 6.46 (1H, dd,J=1.6, 3.4 Hz), 6.84 (2H, br s), 7.21 (2H, dd, J=1.6, 4.4 Hz), 7.57 (1H,dd, J=0.8, 1.6 Hz), 8.55 (2H, dd, J=1.6, 4.4 Hz); MS m/e (FAB) 295(MH⁺).

Example 11 4-(2-Furyl)-6-methyl-5-(4-pyridyl)-2-pyrimidinylaminehydrochloride

The title compound was synthesized in a similar manner to Method 2 ofReference Example 10 using (E)-4-(2-furyl)-3-(4-pyridyl)-3-buten-2-one.¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.09 (3H, s), 6.53 (1H, dd, J=1.6, 3.6Hz), 6.66 (1H, dd, J=0.8, 3.6 Hz), 7.63 (1H, dd, J=0.8, 1.6 Hz), 7.85(2H, dd, J=1.2, 5.2 Hz), 8.90 (2H, dd, J=1.2, 5.2 Hz).

Example 12 4,6-Di(2-furyl)-5-(4-pyridyl)-2-pyrimidinylamine

After dissolving sodium (540 mg, 23.5 mmol) in anhydrous ethanol (200ml), 1-(2-furyl)-2-(4-pyridyl)-1-ethanone (2.00 g, 10.7 mmol) and2-furaldehyde (0.97 ml, 11.7 mmol) were successively added thereto andthe mixture was stirred at room temperature. After 1.5 hours, guanidinehydrochloride (7.0 g, 73.3 mmol) was added thereto, followed by heatingunder reflux for 14 hours. After cooling as it was, the reaction mixturewas concentrated and the residue was suspended in tetrahydrofuran. Then,the insoluble matters were filtered off and washed with tetrahydrofuran,and the solvent of the filtrate was evaporated. To the residue wereadded tetrahydrofuran (80 ml) and active manganese dioxide (30.0 g),followed by heating under reflux for 2 hours. After cooling as it was,the manganese dioxide was filtered off through Celite and washed withtetrahydrofuran. The combined filtrates were concentrated, and thenmethanol was added to the residue. The resulting precipitates werecollected by filtration and washed with methanol, to give the titlecompound (1.32 g, 41%) as a pale brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.06 (2H, dd, J=0.8, 3.4 Hz), 6.44 (2H,dd, J=1.8, 3.4 Hz), 6.96 (2H, br s), 7.33 (2H, dd, J=1.6, 4.4 Hz), 7.65(2H, dd, J=0.8, 1.8 Hz), 8.66 (2H, dd, J=1.6, 4.4 Hz).

Example 13 4-(2-Furyl)-6-phenyl-5-(4-pyridyl)-2-pyrimidinylamine

The title compound was synthesized in a similar manner to Example 12using benzaldehyde.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.19 (1H, dd, J=0.8, 3.6 Hz), 6.46 (1H,dd, J=1.6, 3.6 Hz), 6.99 (2H, br s), 7.14 (2H, dd, J=1.6, 4.4 Hz),7.17-7.27 (5H, m), 7.64 (1H, dd, J=0.8, 1.6 Hz), 8.43 (2H, dd, J=1.6,4.4 Hz).

Example 14 5-(6-Chloro-3-pyridyl)-4-(2-furyl)-2-pyrimidinylamine

A suspension of2-(6-chloro-3-pyridyl)-3-(dimethylamino)-1-(2-furyl)-2-propen-1-one(7.49 g, 27.1 mmol), guanidine hydrochloride (7.7 g, 81.0 mmol) andpotassium carbonate (22.4 g, 162 mmol) in N,N-dimethylformamide (105 ml)was stirred at 70° C. for 21 hours. After cooling as it was, thereaction mixture was diluted with water. The resulting crystals werecollected by filtration and washed with water, to give the titlecompound (5.48 g, 74%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.56 (1H, dd, J=1.6, 3.6 Hz), 6.71 (1H,dd, J=0.8, 3.6 Hz), 6.96 (2H, br s), 7.55 (1H, dd, J=0.6, 8.4 Hz), 7.69(1H, dd, J=0.8, 1.6 Hz), 7.77 (1H, dd, J=2.8, 8.4 Hz), 8.22 (1H, s),8.31 (1H, dd, J=0.6, 2.8 Hz).

Example 155-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

After sodium (455 mg, 19.8 mmol) was dissolved in 4-methoxybenzylalcohol (15 ml) at 90° C. under an atmosphere of nitrogen gas,5-(6-chloro-3-pyridyl)-4-(2-furyl)-2-pyrimidinylamine (1.80 g, 6.60mmol) was added thereto and the mixture was stirred as it was. After 1.5hours, the reaction mixture was cooled as it was and then diluted withan aqueous saturated ammonium chloride solution and ethyl acetate. Theresulting organic layer was washed with an aqueous saturated ammoniumchloride solution, dried over anhydrous sodium sulfate and concentrated.Trifluoroacetic acid (40 ml) was added to the residue, followed bystirring at 65° C. After 18 hours, the reaction mixture was cooled as itwas and diluted with dichloromethane, water and 5N hydrochloride. Theresulting aqueous layer was washed with ethyl acetate and adjusted to pH6 with 5N sodium hydroxide. The resulting crystals were collected byfiltration and washed with water, to give crude crystals of the titlecompound. The resulting crude crystals were suspended in ethyl acetate,collected by filtration and washed with ethyl acetate, to give the titlecompound (820 mg, 49%) as a colorless solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.33 (1H, d, J=9.2 Hz), 6.58 (1H, dd,J=1.8, 3.6 Hz), 6.69 (1H, dd, J=0.8, 3.6 Hz), 6.79 (2H, br s), 7.24 (1H,dd, J=2.8., 9.2 Hz), 7.34 (1H, d, J=2.8 Hz), 7.77 (1H, dd, J=0.8, 1.8Hz), 8.12 (1H, s); MS m/e (ESI) 255 (MH⁺).

Example 165-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone

To a suspension of5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone (2.2 g,8.65 mmol) in methanol (44 ml) was added sodium methoxide (940 mg, 17.4mmol) at room temperature under an atmosphere of nitrogen gas, followedby stirring. After 15 minutes, iodomethane (1.6 ml, 25.7 mmol) was addedthereto, followed by stirring as it was for 22 hours. Afterconcentrating the reaction mixture, water was added to the residue.Then, the precipitates were collected by filtration and washed withwater, to give the crude crystals of the title compound (1.98 g). Thecrude crystals were suspended in ethanol, and then the precipitates werecollected by filtration and washed with ethanol, to give the titlecompound (1.54 g, 66%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.46 (3H, s), 6.38 (1H, d, J=9.2 Hz),6.58 (1H, dd, J=1.6, 3.6 Hz), 6.73 (1H, dd, J=0.8, 3.6 Hz), 6.81 (2H, brs), 7.21 (1H, dd, J=2.6, 9.2 Hz), 7.75 (1H, d, J=2.6 Hz), 7.77 (1H, dd,J=0.8, 1.6 Hz), 8.14 (1H, s); MS m/e (ESI) 269 (MH⁺).

Example 175-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-ethyl-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 16using ethyl iodide.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.24 (3H, t, J=7.2 Hz), 3.93 (2H, q,J=7.2 Hz), 6.38 (1H, d, J=9.2 Hz), 6.58 (1H, dd, J=1.6, 3.2 Hz), 6.71(1H, d, J=3.2 Hz), 6.82 (2H, br s), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.73(1H, d, J=2.8 Hz), 7.78 (1H, d, J=1.6 Hz), 8.17 (1H, s); MS m/e (ESI)283 (MH⁺).

Example 181-Allyl-5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 16using allyl bromide.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.53 (2H, d, J=5.2 Hz), 5.10 (1H, dd,J=1.6, 17.2 Hz), 5.19 (1H, dd, J=1.6, 10.4 Hz), 5.97 (1H, ddt, J=5.2,10.4, 17.2 Hz), 6.42 (1H, d, J=9.2 Hz), 6.58 (1H, dd, J=1.8, 3.6 Hz),6.73 (1H, dd, J=0.8, 3.6 Hz), 6.82 (2H, br s), 7.27 (1H, dd, J=2.2, 9.2Hz), 7.64 (1H, d, J=2.2 Hz), 7.76 (1H, dd, J=0.8, 1.8 Hz), 8.14 (1H, s).

Example 195-[2-Amino-4-(2-thienyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 15using 5-(6-chloro-3-pyridyl)-4-(2-thienyl)-2-pyrimidinylamine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.36 (1H, d, J=9.2 Hz), 6.77 (2H, brs), 7.05 (1H, dd, J=3.6, 4.8 Hz), 7.13 (1H, dd, J=1.2, 3.6 Hz), 7.26(1H, dd, J=2.4, 9.2 Hz), 7.39 (1H, d, J=2.4 Hz), 7.68 (1H, dd, J=1.2,4.8 Hz), 8.10 (1H, s).

Example 205-[2-Amino-4-(2-thienyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 16using 5-[2-amino-4-(2-thienyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.46 (3H, s), 6.41 (1H, d, J=9.2 Hz),6.80 (2H, br s), 7.05 (1H, dd, J=3.8, 5.2 Hz), 7.16 (1H, dd, J=1.0, 3.8Hz), 7.24 (1H, dd, J=2.8, 9.2 Hz), 7.68 (1H, dd, J=1.0, 5.2 Hz), 7.80(1H, d, J=2.8 Hz), 8.12 (1H, s).

Example 215-[2-Amino-4-(3-fluorophenyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 15using 5-(6-chloro-3-pyridyl)-4-(3-fluorophenyl)-2-pyrimidinylamine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.19 (1H, d, J=9.6 Hz), 6.86 (2H, brs), 7.00 (1H, dd, J=2.8, 9.6 Hz), 7.15-7.30 (4H, m), 7.36-7.46 (1H, m),8.26 (1H, s), 11.68 (1H, br s); MS m/e (ESI) 283 (MH⁺).

Example 225-[2-Amino-4-(3-fluorophenyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 16using5-[2-amino-4-(3-fluorophenyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.42 (3H, s), 6.21 (1H, d, J=9.6 Hz),6.87 (1H, dd, J=2.8, 9.6 Hz), 6.89 (2H, br s), 7.20-7.29 (3H, m),7.37-7.44 (1H, m), 7.75 (1H, d, J=2.8 Hz), 8.28 (1H, s).

Example 23 5-(2-Amino-4-phenyl-5-pyrimidinyl)-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 15using 5-(6-chloro-3-pyridyl)-4-phenyl-2-pyrimidinylamine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.16 (1H, d, J=9.6 Hz), 6.80 (2H, brs), 6.96 (1H, dd, J=2.6, 9.6 Hz), 7.23 (1H, d, J=2.6 Hz), 7.34-7.44 (5H,m), 8.23 (1H, s).

Example 245-(2-Amino-4-phenyl-5-pyrimidinyl)-1-methyl-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 16using 5-(2-amino-4-phenyl-5-pyrimidinyl)-1,2-dihydro-2-pyridinone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.42 (3H, s), 6.18 (1H, d, J=9.2 Hz),6.82 (1H, dd, J=2.4, 9.2 Hz), 6.83 (2H, br s), 7.32-7.47 (5H, m), 7.74(1H, d, J=2.4 Hz), 8.25 (1H, s).

Example 25 5-(6-Chloro-3-pyridyl)-4,6-di(2-furyl)-2-pyrimidinylamine

The title compound was synthesized in a similar manner to Example 12using 2-(6-chloro-3-pyridyl)-1-(2-furyl)-1-ethanone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.21 (2H, dd, J=0.6, 3.4 Hz), 6.49 (2H,dd, J=1.8, 3.4 Hz), 6.97 (2H, br s), 7.62 (1H, d, J=8.4 Hz), 7.67 (2H,dd, J=0.6, 1.8 Hz), 7.80 (1H, dd, J=2.4, 8.4 Hz), 8.28 (1H, d, J=2.4Hz).

Example 265-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 15using 5-(6-chloro-3-pyridyl)-4,6-di(2-furyl)-2-pyrimidinylamine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.36 (2H, dd, J=0.8, 3.6 Hz), 6.46 (1H,d, J=9.2 Hz), 6.55 (2H, dd, J=1.6, 3.6 Hz), 6.67 (2H, br s), 7.24 (1H,d, J=2.2 Hz), 7.31 (1H, dd, J=2.2, 9.2 Hz), 7.78 (2H, dd, J=0.8, 1.6Hz), 11.76 (1H, s); MS m/e (ESI) 321 (MH⁺).

Example 275-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 16using5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.43 (3H, s), 6.39 (2H, dd, J=0.8, 3.6Hz), 6.52 (1H, d, J=9.2 Hz), 6.54 (2H, dd, J=1.8, 3.6 Hz), 6.88 (2H, brs), 7.32 (1H, dd, J=2.6, 9.2 Hz), 7.64 (1H, d, J=2.6 Hz), 7.77 (2H, dd,J=0.8, 1.8 Hz); MS m/e (ESI) 335 (MH⁺).

Example 286-(3-Fluorophenyl)-5-(6-methoxy-3-pyridyl)-2,4-pyrimidinediamine

The title compound was synthesized in a similar manner to Method 2 ofReference Example 12 using(E)-3-(3-fluorophenyl)-2-(6-methoxy-3-pyridyl)-2-propenenitrile.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.81 (3H, s), 5.96 (2H, br s), 6.12(2H, br s), 6.74 (1H, d, J=8.6 Hz), 6.92-7.06 (3H, m), 7.18-7.24 (1H,m), 7.41 (1H, dd, J=2.4, 8.6 Hz), 7.80 (1H, d, J=2.4 Hz).

Example 295-[2,4-Diamino-6-(3-fluorophenyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

A solution of6-(3-fluorophenyl)-5-(6-methoxy-3-pyridyl)-2,4-pyrimidinediamine (5.00g, 16.1 mmol) in acetic acid (30 ml)/concentrated hydrobromic acid (50ml) was stirred at 100° C. for 1.5 hours. After cooling as it was, thereaction mixture was adjusted to pH 12 to 13 with 5N sodium hydroxideand washed with ethylacetate. The aqueous layer was neutralized with 5Nhydrochloric acid. The resulting solid was collected by filtration, togive the title compound (3.36 g, 70%) as a colorless solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.06 (2H, br s), 6.07 (2H, br s), 6.21(1H, d, J=9.2 Hz), 6.97 (1H, d, J=2.4 Hz), 7.01-7.09 (4H, m), 7.23-7.30(1H, m); MS m/e (ESI) 298 (MH⁺).

Example 305-[2,4-Diamino-6-(3-fluorophenyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 16using5-[2,4-diamino-6-(3-fluorophenyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.32 (3H, s), 6.07 (2H, br s), 6.17(2H, br s), 6.23 (1H, d, J=9.4 Hz), 6.94 (1H, dd, J=2.6, 9.4 Hz),7.02-7.12 (3H, m), 7.23-7.30 (1H, m), 7.46 (1H, d, J=2.6 Hz); MS m/e(ESI) 312 (MH⁺).

Example 31 5-[6-(Benzyloxy)-3-pyridyl]-4-(2-furyl)-2-pyrimidinylamine

A solution of 5-bromo-4-(2-furyl)-2-pyrimidinylamine (10.5 g, 43.9mmol), 2-(benzyloxy)-5-(1, 1, 1-tributylstanyl)-pyridine (41.7 g, 87.9mmol) and dichlorobis-(triphenylphosphine)palladium (II) (1.6 g, 2.28mmol) in N,N-dimethylformamide (100 ml) was stirred at 100° C. for 25hours under an atmosphere of nitrogen gas. After cooling as it was, thereaction mixture was diluted with ethyl acetate and an aqueous saturatedammonium chloride solution. The insoluble matters were filtered off, andthen the organic layer in the filtrate was washed with an aqueoussaturated ammonium chloride solution twice, dried over anhydrousmagnesium sulfate and concentrated. The residue was suspended in hexane,and then the solid was collected by filtration and washed with hexane.The obtained solid was suspended in ethyl acetate, and then collected byfiltration and washed with ethyl acetate, to give the title compound(8.35 g, 55%) as a pale orange solid.

¹H NMR (400 MHz, DMSO-d₆) 6ppm; 5.36 (2H, s), 6.50 (1H, dd, J=0.8, 3.4Hz), 6.52 (1H, dd, J=1.8, 3.4 Hz), 6.82 (2H, br s), 6.90 (1H, dd, J=0.6,8.4 Hz), 7.30-7.35 (1H, m), 7.36-7.41 (2H, m), 7.44-7.49 (2H, m), 7.59(1H, dd, J=2.6, 8.4 Hz), 6.68 (1H, dd, J=0.8, 1.8 Hz), 8.06 (1H, dd,J=0.6, 2.6 Hz), 8.14 (1H, s).

Example 32 (Alternative Synthetic Method of Example 15)5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

A suspension of5-[6-(benzyloxy)-3-pyridyl]-4-(2-furyl)-2-pyrimidinylamine (8.35 g, 24.2mmol) in concentrated hydrochloric acid (40 ml)-water (40 ml) wasstirred at 80° C. for 1 hour. After cooling as it was, the reactionmixture was washed with ethyl acetate twice. The aqueous layer wasneutralized with an aqueous 5N sodium hydroxide solution. The resultingsolid was collected by filtration, washed with water and dried at 50° C.for 14 hours, to give the title compound (5.54 g, 90%) as a pale brownsolid.

Example 33 5-[6-(Benzyloxy)-3-pyridyl]-4,6-di(2-furyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 31using 5-bromo-4,6-di(2-furyl)-2-pyrimidinamine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 5.42 (2H, s), 5.93 (2H, dd, J=0.4, 3.6Hz), 6.44 (2H, dd, J=1.6, 3.6 Hz), 6.88 (2H, br s), 7.01 (1H, dd, J=0.4,8.8 Hz), 7.30-7.51 (5H, m), 7.62 (1H, dd, J=2.4, 8.8 Hz), 7.67 (2H, dd,J=0.4, 1.6 Hz), 7.97 (1H, d, J=2.4 Hz).

Example 34 5-(2-Fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 12using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.33 (2H, dd, J=0.8, 3.6 Hz), 6.48 (2H,dd, J=1.6, 3.6 Hz), 6.99 (2H, br s), 7.21 (1H, br), 7.28-7.32 (1H, m),7.65 (2H, dd, J=0.8, 1.6 Hz), 8.31 (1H, d, J=5.2 Hz).

Example 355-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(3-furyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 12using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and 3-furaldehyde.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.31 (1H, dd, J=0.8, 2.0 Hz), 6.37 (1H,dd, J=0.8, 3.6 Hz), 6.47 (1H, dd, J=1.6, 3.6 Hz), 6.91 (2H, br s),7.17-7.18 (2H, m), 7.26-7.30 (1H, m), 7.58 (1H, dd, J=1.6, 2.0 Hz), 7.62(1H, dd, J=0.8, 1.6 Hz), 8.30 (1H, d, J=4.8 Hz).

Example 365-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(2-thienyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 12using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and2-thiophenecarboxyaldehyde.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.35 (1H, d, J=3.6 Hz), 6.42 (1H, dd,J=0.8, 3.6 Hz), 6.48 (1H, dd, J=1.6, 3.6 Hz), 6.91 (1H, dd, J=3.6, 5.2Hz), 6.95 (2H, br s), 7.27 (1H, br), 7.34-7.38 (1H, m), 7.61-7.66 (2H,m), 8.34 (1H, d, J=4.8 Hz).

Example 375-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(3-thienyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 12using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and3-thiophenecarboxyaldehyde.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.39 (1H, dd, J=0.8, 3.6 Hz), 6.48 (1H,dd, J=1.6, 3.6 Hz), 6.94-6.97 (3H, m), 7.07 (1H, br), 7.18-7.20 (1H, m),7.27 (1H, dd, J=1.2, 2.8 Hz), 7.40 (1H, dd, J=2.8, 5.2 Hz), 7.62 (1H,dd, J=0.8, 1.6 Hz), 8.20 (1H, d, J=5.2 Hz).

Example 385-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(2-pyridyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 12using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and2-pyridinecarboxyaldehyde.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.43 (1H, dd, J=0.8, 3.6 Hz), 6.50 (1H,dd, J=2.0, 3.6 Hz), 6.89 (1H, br), 7.02-7.04 (1H, m), 7.09 (2H, br s),7.27 (1H, ddd, J=1.2, 4.8, 7.6 Hz), 7.60 (1H, ddd, J=0.8, 1.2, 7.6 Hz),7.65 (1H, dd, J=0.8, 2.0 Hz), 7.79 (1H, ddd, J=1.6, 7.6, 7.6 Hz), 8.03(1H, d, J=5.2 Hz), 8.27 (1H, ddd, J=0.8, 1.6, 4.8 Hz).

Example 395-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(3-pyridyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 12using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and3-pyridinecarboxyaldehyde.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.48 (1H, d, J=3.6 Hz), 6.51 (1H, dd,J=1.6, 3.6 Hz), 7.05 (1H, br), 7.12 (2H, br s), 7.14-7.18 (1H, m), 7.28(1H, dd, J=5.2, 8.0 Hz), 7.60 (1H, ddd, J=1.6, 2.0, 8.0 Hz), 7.65 (1H,dd, J=0.8, 1.6 Hz), 8.10 (1H, d, J=4.8 Hz), 8.39 (1H, d, J=2.0 Hz), 8.45(1H, dd, J=1.6, 5.2 Hz).

Example 405-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-(4-pyridyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 12using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and4-pyridinecarboxyaldehyde.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.48 (1H, d, J=3.6 Hz), 6.51 (1H, dd,J=2.0, 3.6 Hz), 7.05 (1H, s), 7.12-7.18 (1H, m), 7.15 (2H, br s), 7.19(2H, dd, J=1.6, 4.4 Hz), 7.63-7.67 (1H, m), 8.10 (1H, d, J=5.6 Hz), 8.46(2H, dd, J=1.6, 4.4 Hz).

Example 41 5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-6-phenyl-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 12using 2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone and benzaldehyde.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.44 (1H, d, J=3.2 Hz), 6.49 (1H, dd,J=1.6, 3.2 Hz), 6.97 (1H, br), 7.02 (2H, br s), 7.07-7.12 (1H, m),7.16-7.29 (5H, m), 7.60-7.64 (1H, m), 8.07 (1H, d, J=5.2 Hz).

Example 42 5-(2-Bromo-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 12using 2-(2-bromo-4-pyridyl)-1-(2-furyl)-1-ethanone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.33 (2H, dd, J=0.8, 3.6 Hz), 6.49 (2H,dd, J=1.6, 3.6 Hz), 6.97 (2H, br s), 7.40 (1H, dd, J=1.6, 4.8 Hz), 7.63(1H, dd, J=0.8, 1.6 Hz), 7.64 (2H, dd, J=0.8, 1.6 Hz), 8.44 (1H, dd,J=0.8, 4.8 Hz).

Example 435-[2-(Dimethylamino)-4-pyridyl]-4,6-di(2-furyl)-2-pyrimidinamine

In an autoclave, 5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine(200 mg, 0.621 mmol) was suspended in 1,2-dimethoxyethane (10 ml) andthen a 50% dimethylamine aqueous solution (5 ml) was added thereto,followed by stirring at 70° C. After 11 hours, the reaction mixture wasextracted with ethyl acetate, and the extract was washed with water andbrine, dried over anhydrous sodium sulfate and then the filtrate wasconcentrated. The resulting solid was suspended in ethanol, collected byfiltration and washed with ethanol, to give the title compound (92 mg,43%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.99 (6H, s), 6.02 (2H, d, J=3.2 Hz),6.44 (2H, dd, J=1.6, 3.2 Hz), 6.49 (1H, dd, J=1.2, 4.8 Hz), 6.54 (1H,s), 6.86 (2H, br s), 7.70 (2H, d, J=1.6 Hz), 8.17 (1H, d, J=4.8 Hz).

Example 44 4,6-Di(furyl)-5-[2-(methylamino)-4-pyridyl]-2-pyridinamine

The title compound was synthesized in a similar manner to Example 43 at70 to 80° C. using a 40% methylamine aqueous solution.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.78 (3H, d, J=5.2 Hz), 6.07 (2H, d,J=3.6 Hz), 6.30 (1H, s), 6.41 (1H, dd, J=1.2, 5.2 Hz), 6.46 (2H, dd,J=2.0, 3.6 Hz), 6.51 (1H, q, J=5.2 Hz), 6.86 (2H, br s), 7.71 (2H, d,J=2.0 Hz), 8.08 (1H, d, J=5.2 Hz).

Example 45 5-[2-(Ethylamino)-4-pyridyl]-4,6-di(2-furyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 43 at80° C. from a 70% ethylamine aqueous solution.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.12 (3H, t, J=7.2 Hz), 3.23-3.30 (2H,m), 6.07 (2H, dd, J=0.8, 3.2 Hz), 6.30 (1H, dd, J=0.8, 1.2 Hz), 6.41(1H, dd, J=1.2, 4.8 Hz), 6.46 (2H, dd, J=1.6, 3.2 Hz), 6.47 (1H, t,J=3.2 Hz), 6.86 (2H, br s), 7.72 (2H, dd, J=0.8, 1.6 Hz), 8.07 (1H, dd,J=0.8, 4.8 Hz).

Example 464,6-Di(2-furyl)-5-[2-(propylamino)-4-pyridyl]-2-pyrimidinamine

In a reaction vessel,5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine (200 mg, 0.621mmol) and n-propylamine (5 ml) were mixed together and the mixture wasstirred at 120° C. After 18 hours, the reaction mixture was extractedwith ethyl acetate, and the extract was washed with water and brine,dried over anhydrous sodium sulfate and then the filtrate wasconcentrated. The resulting solid was suspended in ethanol, collected byfiltration and washed with ethanol, to give the title compound (64%,72mg) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 0.89 (3H, t, J=7.2 Hz), 1.47-1.57 (2H,m), 3.18-3.23 (2H, m), 6.07 (2H, dd, J=0.8, 3.2 Hz), 6.31-6.32 (1H, m),6.39 (1H, dd, J=1.2, 5.2 Hz), 6.46 (2H, dd, J=1.6, 3.2 Hz), 6.51 (1H, t,J=5.6 Hz), 6.86 (2H, br s), 7.72 (2H, dd, J=0.8, 1.6 Hz), 8.06 (1H, dd,J=0.8, 5.2 Hz).

Example 47 5-[2-(Butylamino)-4-pyridyl]-4,6-di(2-furyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 46 at80 to 120° C. using n-butylamine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 0.89 (3H, t, J=7.2 Hz), 1.28-1.37 (2H,m), 1.45-1.53 (2H, m), 3.21-3.26 (2H, m), 6.07 (2H, dd, J=0.8, 3.6 Hz),6.29-6.30 (1H, m), 6.39 (1H, dd, J=1.2, 5.2 Hz), 6.46 (2H, dd, J=1.6,3.6 Hz), 6.48 (1H, t, J=5.2 Hz), 6.86 (2H, br s), 7.71 (2H, dd, J=0.8,1.6 Hz), 8.06 (1H, dd, J=0.8, 5.2 Hz).

Example 484,6-Di(2-furyl)-5-[2-(isopropylamino)-4-pyridyl]-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 46 at120 to 200° C. using i-propylamine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.13 (6H, d, J.=6.8 Hz), 3.97-4.05 (1H,m), 6.07 (2H, dd, J=0.8, 3.2 Hz), 6.28 (1H, s), 6.31 (1H, d, J=7.2 Hz),6.39 (1H, dd, J=1.2, 5.2 Hz), 6.46 (2H, dd, J=1.6, 3.2 Hz), 6.86 (2H, brs), 7.72 (2H, dd, J=0.8, 1.6 Hz), 8.07 (1H, d, J=5.2 Hz).

Example 49 5-(2-Amino-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 43 at80 to 120° C. using 28% aqueous ammonia.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 5.98 (2H, br s), 6.08 (2H, d, J=3.2Hz), 6.29 (1H, br), 6.42 (1H, d, J=5.2 Hz), 6.46 (2H, dd, J=1.6, 3.2Hz), 6.86 (2H, br s), 7.72 (2H, br), 8.01 (1H, d, J=5.2 Hz).

Example 502-(4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridylamino)-1-ethanol

The title compound was synthesized in a similar manner to Example 46 at120° C. using ethanolamine.

¹H NMR (400 MHz, CDCl₃) δ ppm; 3.57 (2H, td, J=4.4, 5.2 Hz), 3.84 (2H,t, J=4.4 Hz), 4.88 (1H, t, J=5.2 Hz), 5.28 (2H, br s), 6.08 (2H, dd,J=0.4, 3.6 Hz), 6.33 (2H, dd, J=1.6, 3.6 Hz), 6.38 (1H, br), 6.59 (1H,dd, J=1.2, 5.2 Hz), 7.48 (2H, d, J=1.6 Hz), 8.18 (1H, d, J=5.2 Hz).

Example 515-[2-(Benzylamino)-4-pyridyl]-4,6-di(2-furyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 46 at120° C. using benzylamine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.52 (2H, d, J=6.0 Hz), 6.05 (2H, dd,J=0.8, 3.6 Hz), 6.39 (1H, br), 6.43 (1H, dd, J=1.6, 5.2 Hz), 6.46 (2H,dd, J=1.6, 3.6 Hz), 6.86 (2H, br s), 7.07 (1H, t, J=6.0 Hz), 7.17-7.21(1H, m), 7.26-7.31 (4H, m), 7.71 (2H, dd, J=0.8, 1.6 Hz), 8.06 (1H, dd,J=0.8, 5.2 Hz).

Example 521-{4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-4-piperidinol

The title compound was synthesized in a similar manner to Example 46 at120° C. using 4-hydroxypiperidine in 1-methyl-2-pyrrolidinone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.25-1.33 (2H, m), 1.69-1.72 (2H, m),3.03-3.09 (2H, m), 3.67 (1H, br), 3.96-3.99 (2H, m), 4.67 (1H, br d,J=3.2 Hz), 6.03 (2H, dd, J=0.8, 3.2 Hz), 6.44 (2H, dd, J=1.6, 3.2 Hz),6.51 (1H, dd, J=1.2, 5.2 Hz), 6.76 (1H, br), 6.86 (2H, br s), 7.70 (2H,dd, J=0.8, 1.6 Hz), 8.18 (1H, d, J=5.2 Hz).

Example 53 Ethyl1-{4-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-4-piperidinecarboxylate

The title compound was synthesized in a similar manner to Example 46 at120° C. using ethyl isonipecotate.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.17 (3H, t, J=7.2 Hz), 1.44-1.53 (2H,m), 1.78-1.80 (2H, m), 2.56-2.62 (1H, m), 2.90-2.96 (2H, m), 4.06 (2H,t, J=7.2 Hz), 4.16-4.19 (2H, m), 6.04 (2H, d, J=3.2 Hz), 6.43 (2H, dd,J=1.2, 3.2 Hz), 6.54 (1H, dd, J=0.8, 4.8 Hz), 6.78 (1H, br), 6.87 (2H,br s), 7.69 (2H, d, J=1.2 Hz), 8.19 (1H, d, J=4.8 Hz).

Example 54N1-{4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-1,2-ethanediamine

The title compound was synthesized in a similar manner to Example 46using ethylenediamine under reflux.

¹H NMR (400 MHz, CDCl₃) δ ppm; 2.93 (2H, t, J=5.6 Hz), 3.36 (2H, td,J=5.6, 5.6 Hz), 4.96 (1H, br t, J=5.6 Hz), 5.30 (2H, br s), 6.06 (2H,dd, J=0.8, 3.6 Hz), 6.31 (2H, dd, J=2.0, 3.6 Hz), 6.34-6.35 (1H, m),6.55 (1H, dd, J=1.6, 5.2 Hz), 7.49 (2H, dd, J=0.8, 2.0 Hz), 8.22 (1H,dd, J=0.8, 5.2 Hz).

Example 55N1-{4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-1,3-propanediamine

The title compound was synthesized in a similar manner to Example 46 at120° C. using 1,3-diaminopropane.

1H NMR (400 MHz, CDCl₃) δ ppm; 1.74 (2H, tt, J=6.8, 6.8 Hz), 2.83 (2H,t, J=6.8 Hz), 3.37 (2H, dt, J=5.2, 6.8 Hz), 5.08 (1H, br t, J=5.2 Hz),5.28 (2H, br s), 6.06 (2H, dd, J=0.8, 3.6 Hz), 6.30-6.32 (1H, m), 6.31(2H, dd, J=1.6, 3.6 Hz), 6.53 (1H, dd, J=1.6, 5.2 Hz), 7.49 (2H, dd,J=0.8, 1.6 Hz), 8.21 (1H, dd, J=0.8, 5.2 Hz).

Example 56N1-{4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-1,4-butanediamine

The title compound was synthesized in a similar manner to Example 46 at120° C. using 1,4-diaminobutane.

¹H NMR (400 MHz, CDCl₃) δ ppm; 1.49-1.68 (4H, m), 2.71 (2H, t, J=6.8Hz), 3.27 (2H, t, J=6.4 Hz), 4.77 (1H, br), 5.29 (2H, br s), 6.06 (2H,dd, J=0.8, 3.6 Hz), 6.30-6.32 (1H, m), 6.31 (2H, dd, J=1.6, 3.6 Hz),6.54 (1H, dd, J=1.2, 5.2 Hz), 7.49 (2H, dd, J=0.8, 1.6 Hz), 8.21 (1H,dd, J=0.8, 5.2 Hz).

Example 575-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-(3-furyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 43 at80° C. using5-(2-fluoro-4-pyridyl)-4-(2-furyl)-6-(3-furyl)-2-pyrimidinamine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.99 (6H, s), 6.07 (1H, d, J=3.6 Hz),6.44-6.46 (2H, m), 6.48 (1H, dd, J=1.2, 4.8 Hz), 6.53 (1H, s), 6.76 (2H,br s), 7.14 (1H, s), 7.58 (1H, dd, J=1.2, 1.2 Hz), 7.70 (1H, d, J=1.6Hz), 8.17 (1H, d, J=5.2 Hz).

Example 585-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-(2-thienyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 43 at80° C. using5-(2-fluoro-4-pyridyl)-4-(2-furyl)-6-(2-thienyl)-2-pyrimidinamine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.00 (6H, s), 6.02 (1H, dd, J=0.8, 3.6Hz), 6.45 (1H, dd, J=2.0, 3.6 Hz), 6.52 (1H, dd, J=1.2, 5.2 Hz), 6.59(1H, s), 6.62 (1H, dd, J=1.2, 4.0 Hz), 6.81 (2H, br s), 6.91 (1H, dd, J4.0, 5.2 Hz), 7.59 (1H, dd, J=1.2, 5.2 Hz), 7.71 (1H, dd, J=0.8, 2.0Hz), 8.20 (1H, dd, J=0.8, 5.2 Hz).

Example 595-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-(3-thienyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 43 at80° C. using5-(2-fluoro-4-pyridyl)-4-(2-furyl)-6-(3-thienyl)-2-pyrimidinamine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.94 (6H, s), 6.06 (1H, d, J=3.2 Hz),6.39-6.46 (3H, m), 6.78 (2H, br s), 7.05 (1H, dd, J=1.2, 4.8 Hz),7.34-7.39 (2H, m), 7.68 (1H, d, J=1.2 Hz), 8.07 (1H, d, J=4.8 Hz).

Example 605-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-(2-pyridyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 43 at80° C. using5-(2-fluoro-4-pyridyl)-4-(2-furyl)-6-(2-pyridyl)-2-pyrimidinamine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.84 (6H, s), 6.19 (1H, dd, J=0.8, 3.2Hz), 6.26 (1H, br), 6.28 (1H, dd, J=1.2, 5.2 Hz), 6.46 (1H, dd, J=1.6,3.2 Hz), 6.95 (2H, br s), 7.25 (1H, ddd, J=1.2, 4.8, 7.6 Hz), 7.38-7.40(1H, m), 7.68-7.73 (2H, m), 7.87 (1H, dd, J=0.4, 5.2 Hz), 8.36-8.38 (1H,m).

Example 615-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-(3-pyridyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 43 at80° C. using5-(2-fluoro-4-pyridyl)-4-(2-furyl)-6-(3-pyridyl)-2-pyrimidinamine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.87 (6H, s), 6.17 (1H, dd, J=0.8, 3.6Hz), 6.36 (1H, dd, J=1.2, 5.2 Hz), 6.39 (1H, br), 6.46 (1H, dd, J=1.6,3.6 Hz), 6.96 (2H, br s), 7.27 (1H, ddd, J=0.8, 5.2, 8.0 Hz), 7.67 (1H,dt, J=2.0, 8.0 Hz), 7.70 (1H, dd, J=0.8, 1.6 Hz), 7.94 (1H, d, J=5.2Hz), 8.41-8.45 (2H, m).

Example 625-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-(4-pyridyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 43 at80° C. using5-(2-fluoro-4-pyridyl)-4-(2-furyl)-6-(4-pyridyl)-2-pyrimidinamine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.88 (6H, s), 6.17 (1H, d, J=3.6 Hz),6.36 (1H, d, J=5.2 Hz), 6.39 (1H, s), 6.47 (1H, dd, J=1.6, 3.6 Hz), 7.01(2H, br s), 7.24 (2H, d, J=5.6 Hz), 7.72 (1H, s), 7.95 (1H, d, J=5.2Hz), 8.44 (2H, d, J=5.6 Hz).

Example 635-[2-(Dimethylamino)-4-pyridyl]-4-(2-furyl)-6-phenyl-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 43 at80° C. using5-(2-fluoro-4-pyridyl)-4-(2-furyl)-6-phenyl-2-pyrimidinamine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.84 (6H, s), 6.12 (1H, d, J=3.2 Hz),6.31 (1H, br), 6.32 (1H, br), 6.44 (1H, dd, J=1.6, 3.2 Hz), 6.85 (2H, brs), 7.19-7.26 (5H, m), 7.67-7.68 (1H, m), 7.91 (1H, d, J=5.6 Hz).

Example 64 5-(2-Butoxy-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine

In a reaction vessel, sodium (21 mg, 0.931 mmol) was dissolved inn-butanol (4 ml) and then5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine (100 mg, 0.310mmol) was added thereto, followed by stirring under reflux for 5 hoursunder an atmosphere of nitrogen gas. The reaction was terminated byadding water thereto. Then, the reaction mixture was extracted withethyl acetate, washed with water and brine, dried over anhydrous sodiumsulfate and then the filtrate was concentrated. The resulting solid wassuspended in ethanol, collected by filtration and washed with ethanol,to give the title compound (63 mg, 54%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 0.92 (3H, t, J=7.2 Hz), 1.36-1.45 (2H,m), 1.66-1.73 (2H, m), 4.29 (2H, t, J=6.8 Hz), 6.09 (2H, dd, J=0.8, 3.6Hz), 6.45 (2H, dd, J=1.6, 3.6 Hz), 6.69 (1H, dd, J=0.8, 1.6 Hz), 6.90(1H, dd, J=1.6, 5.2 Hz), 6.91 (2H, br s), 7.66 (2H, dd, J=0.8, 1.6 Hz),8.22 (1H, dd, J=0.8, 5.2 Hz).

Example 652-({4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}oxy)-1-ethanol

In a reaction vessel, sodium hydride (15 mg, 0.372 mmol) was suspendedin N,N-dimethylformamide (4 ml) and ethylene glycol (23 mg, 0.372 mmol)was added thereto, followed by stirring at 80° C. for 30 minutes underan atmosphere of nitrogen gas. Subsequently,5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine (100 mg, 0.310mmol) was added thereto, followed by stirring for 14 hours under thesame conditions. Then, the reaction was terminated by adding waterthereto. The reaction mixture was extracted with ethyl acetate, washedwith water and brine, dried over anhydrous sodium sulfate and then thefiltrate was concentrated. The resulting crude product was purified bysilica gel column chromatography, to give the title compound (41 mg,36%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.71 (2H, td, J=5.2, 5.2 Hz), 4.30 (2H,t, J=5.2 Hz), 4.84 (1H, t, J=5.2 Hz), 6.09 (2H, d, J=3.2 Hz), 6.45 (2H,dd, J=1.6, 3.2 Hz), 6.71 (1H, br), 6.91-6.92 (3H, m), 7.66 (2H, d, J=1.6Hz), 8.22 (1H, d, J=5.2 Hz).

Example 665-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-propyl-1,2-dihydro-2-pyridinone

In a reaction vessel,5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone (100 mg,0.393 mmol) and potassium carbonate (109 mg, 0.787 mmol) were suspendedin methanol (2 ml). Then, propyl iodide (134 mg, 0.787 mmol) was addedthereto, followed by stirring at 50° C. for 17 hours. After the reactionwas terminated, the mixture was concentrated and suspended indimethylsulfoxide. The insoluble matters were removed by filtration andthe resulting filtrate was purified by HPLC, to give the title compound(48 mg, 41%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 0.86 (3H, t, J=7.2 Hz), 1.67 (2H, tq,J=7.2, 7.2 Hz), 3.85 (2H, t, J=7.2 Hz), 6.37 (1H, dd, J=0.4, 9.6 Hz),6.57 (1H, dd, J=1.6, 3.2 Hz), 6.68 (1H, dd, J=0.8, 3.2 Hz), 6.79 (2H, brs), 7.22 (1H, dd, J=2.4, 9.6 Hz), 7.68 (1H, dd, J=0.4, 2.4 Hz), 7.75(1H, dd, J=0.8, 1.6 Hz), 8.13 (1H, s).

Example 675-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-butyl-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using butyl iodide.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 0.89 (3H, t, J=7.2 Hz), 1.28 (2H, tq,J=7.2, 7.2 Hz), 1.63 (2H, dt, J=7.2, 7.2 Hz), 3.88 (2H, t, J=7.2 Hz),6.37 (1H, d, J=9.2 Hz), 6.57 (1H, dd, J=1.6, 3.6 Hz), 6.68 (1H, d, J=3.6Hz), 6.79 (2H, br s), 7.22 (1H, dd, J=2.4, 9.2 Hz), 7.68 (1H, d, J=2.4Hz), 7.73-7.75 (1H, m), 8.13 (1H, s).

Example 685-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-fluoroethyl)-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 1-iodo-2-fluoroethane.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.24 (2H, dt, J=4.8, 26.0 Hz), 4.70(2H, dt, J=4.8, 47.2 Hz), 6.42 (1H, d, J=9.2 Hz), 6.57 (1H, dd, J=1.6,3.6 Hz), 6.70 (1H, dd, J=0.8, 3.6 Hz), 6.81 (2H, br s), 7.27 (1H, dd,J=2.8, 9.2 Hz), 7.68 (1H, d, J=2.8 Hz), 7.74-7.76 (1H, m), 8.11 (1H, s).

Example 695-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(8-hydroxyoctyl)-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 8-bromo-1-octanol.

¹H NMR (400 MHz, MeOH-d₄) δ ppm; 1.20-1.31 (8H, m), 1.37-1.45 (2H, m),1.62-1.71 (2H, m), 3.42 (2H, t, J=6.8 Hz), 3.92 (2H, t, J=7.2 Hz), 6.42(1H, dd, J=2.0, 3.6 Hz), 6.46 (1H, d, J=9.2 Hz), 6.75 (1H, d, J=3.6 Hz),7.27 (1H, dd, J=2.4, 9.2 Hz), 7.46-7.48 (1H, m), 7.53 (1H, d, J=2.4 Hz),8.03 (1H, s).

Example 70 Methyl4-{5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}butanoate

The title compound was synthesized in a similar manner to Example 66using ethyl 4-bromobutylate.

¹H NMR (400 MHz, CDCl₃) δ ppm; 2.12 (2H, tt, J=7.2, 7.2 Hz), 2.41 (2H,t, J=7.2 Hz), 3.67 (3H, s), 4.04 (2H, t, J=7.2 Hz), 5.45 (2H, br s),6.44 (1H, dd, J=1.6, 3.6 Hz), 6.60 (1H, d, J=9.2 Hz), 6.71 (1H, d, J=3.6Hz), 7.20 (1H, dd, J=2.8, 9.2 Hz), 7.24 (1H, d, J=2.8 Hz), 7.49 (1H, dd,J=0.8, 1.6 Hz), 8.14 (1H, s).

Example 715-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-propynyl)-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using propargyl bromide.

¹H NMR (400 MHz, CDCl₃) δ ppm; 2.49 (1H, t, J=2.8 Hz), 4.82 (2H, d,J=2.8 Hz), 5.31 (2H, br s), 6.45 (1H, dd, J=1.6, 3.6 Hz), 6.61 (1H, dd,J=0.4, 9.2 Hz), 6.74 (1H, dd, J=0.8, 3.6 Hz), 7.23 (1H, dd, J=2.4, 9.2Hz), 7.49 (1H, dd, J=0.8, 1.6 Hz), 7.59 (1H, dd, J=0.4, 2.4 Hz), 8.16(1H, s).

Example 725-[2-Amino-4-2-furyl)-5-pyrimidinyl]-1-|isobutyl-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 1-iodo-2-methylpropane.

¹H NMR (400 MHz, CDCl₃) δ ppm; 0.96 (6H, t, J=7.2 Hz), 2.16-2.27 (1H,m), 3.78 (2H, d, J=7.6 Hz), 5.26 (2H, br s), 6.43 (1H, dd, J=1.6, 3.6Hz), 6.61 (1H, d, J=9.6 Hz), 6.68 (1H, dd, J=0.8, 3.6 Hz), 7.14 (1H, dd,J=0.4, 2.4 Hz), 7.19 (1H, dd, J=2.4, 9.6 Hz), 7.48 (1H, dd, J=0.8, 1.6Hz), 8.12 (1H, s).

Example 735-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-butynyl)-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 1-bromo-2-butyne.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.80 (3H, s), 4.67 (2H, d, J=2.0 Hz),6.41 (1H, d, J=9.2 Hz), 6.56-6.59 (1H, m), 6.74 (1H, d, J=3.2 Hz), 6.80(2H, br s), 7.26 (1H, dd, J=2.0, 9.2 Hz), 7.72 (1H, d, J=2.0 Hz), 7.74(1H, br), 8.13 (1H, s).

Example 745-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-benzyl-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using benzyl chloride.

¹H NMR (400 MHz, CDCl₃) δ ppm; 5.14 (2H, br), 5.18 (2H, s), 6.39 (1H,dd, J=1.6, 3.6 Hz), 6.64-6.68 (2H, m), 7.18-7.23 (2H, m), 7.27-7.36 (5H,m), 7.41 (1H, dd, J=0.8, 1.6 Hz), 8.07 (1H, s).

Example 755-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-isopentyl-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 1-iodo-3-methylbutane.

¹H NMR (400 MHz, MeOH-d₄) δ ppm; 0.98 (6H, d, J=6.0 Hz), 1.60-1.70 (3H,m), 4.05 (2H, t, J=7.2 Hz), 6.53 (1H, dd, J=1.6, 3.6 Hz), 6.57 (1H, d,J=9.2 Hz), 6.86 (1H, dd, J=0.4, 3.6 Hz), 7.38 (1H, dd, J=2.8, 9.2 Hz),7.58 (1H, dd, J=0.4, 1.6 Hz), 7.65 (1H, d, J=2.8 Hz), 8.14 (1H, s).

Example 765-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-methylbutyl)-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 1-iodo-2-methylbutane.

¹H NMR (400 MHz, MeOH-d₄) δ ppm; 0.91 (3H, d, J=6.8 Hz), 0.96 (3H, t,J=7.6 Hz), 1.17-1.28 (1H, m), 1.38-1.50(1H, m), 1.93-2.04 (1H, m), 3.79(1H, dd, J=8.4, 12.8 Hz), 3.99 (1H, dd, J=6.8, 12.8 Hz), 6.53 (1H, dd,J=1.6, 3.6 Hz), 6.58 (1H, d, J=9.2 Hz), 6.87 (1H, d, J=3.6 Hz), 7.39(1H, dd, J=2.4, 9.2 Hz), 7.57 (1H, br), 7.60 (1H, d, J=2.4 Hz), 8.12(1H, s).

Example 775-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-octyl-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using octyl bromide.

¹H NMR (400 MHz, CDCl₃) δ ppm; 0.87 (3H, t, J=7.2 Hz), 1.18-1.42 (10H,m), 1.72-1.81 (2H, m), 3.95 (2H, d, J=7.6 Hz), 5.17 (2H, br s), 6.43(1H, dd, J=1.6, 3.6 Hz), 6.60 (1H, d, J=10.4 Hz), 6.66 (1H, dd, J=0.8,3.6 Hz), 7.16-7.22 (2H, m), 7.48-7.51 (1H, m), 8.13 (1H, s).

Example 782-{5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}ethylcyanide

The title compound was synthesized in a similar manner to Example 66using 3-bromopropionitrile.

¹H NMR (400 MHz, CDCl₃) δ ppm; 2.99 (2H, t, J=6.0 Hz), 4.20 (2H, t,J=6.0 Hz), 5.18 (2H, br s), 6.45 (1H, dd, J=1.6, 3.6 Hz), 6.62 (1H, d,J=9.6 Hz), 6.78 (1H, d, J=3.6 Hz), 7.22-7.33 (2H, m), 7.48-7.51 (1H, m),8.16 (1H, s).

Example 795-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-fluoropropyl)-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 1-bromo-3-fluoropropane.

¹H NMR (400 MHz, CDCl₃) δ ppm; 2.21 (2H, dtt, J=6.0, 6.8, 27.2 Hz), 4.12(2H, t, J=6.8 Hz), 4.51 (2H, dt, J=6.0, 46.8 Hz), 5.42 (2H, br s), 6.46(1H, dd, J=1.6, 3.6 Hz), 6.60 (1H, dd, J=0.8, 9.2 Hz), 6.75 (1H, d,J=3.6 Hz), 7.20-7.26 (2H, m), 7.48-7.52 (1H, m), 8.11 (1H, s).

Example 805-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-hydroxyethyl)-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 2-iodoethanol.

MS m/e (ESI) 299 (MH⁺).

Example 815-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-hydroxypropyl)-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 3-iodopropanol.

¹H NMR (400 MHz, MeOH-d₄) δ ppm; 1.98 (2H, dt, J=6.4, 6.4 Hz), 3.60 (2H,t, J=6.4 Hz), 4.14 (2H, t, J=6.4 Hz), 6.54 (1H, dd, J=2.0, 3.6 Hz), 6.58(1H, d, J=9.2 Hz), 6.89 (1H, d, J=3.6 Hz), 7.39 (1H, dd, J=2.4, 9.2 Hz),7.58-7.60 (1H, m), 7.66 (1H, d, J=2.4 Hz), 8.15 (1H, s).

Example 825-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-methoxyethyl)-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 2-bromoethyl methyl ether.

¹H NMR (400 MHz, CDCl₃) δ ppm; 3.30 (3H, s), 3.70 (2H, t, J=4.8 Hz),4.16 (2H, t, J=4.8 Hz), 5.23 (2H, br s), 6.40-6.46 (1H, m), 6.60 (1H, d,J=9.2 Hz), 6.65 (1H, d, J=3.2 Hz), 7.20 (1H, dd, J=2.4, 9.2 Hz), 7.31(1H, d, J=1.6 Hz), 7.50 (1H, br), 8.14 (1H, s).

Example 835-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-[2-(1H-1-pyrrolyl)ethyl]-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 1-(2-bromoethyl)pyrrole.

¹H NMR (400 MHz, CDCl₃) δ ppm; 4.21-4.26 (2H, m), 4.28-4.33 (2H, m),5.12 (2H, br s), 6.12 (2H, dd, J=2.0, 2.0 Hz), 6.37 (1H, d, J=2.4 Hz),6.43 (1H, dd, J=1.6, 3.6 Hz), 6.52 (2H, dd, J=2.0, 2.0 Hz), 6.57 (1H, d,J=9.6 Hz), 6.66 (1H, dd, J=0.8, 3.6 Hz), 7.15 (1H, dd, J=2.4, 9.6 Hz),7.47 (1H, dd, J=0.8, 1.6 Hz), 7.84 (1H, s).

Example 842-{5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}acetamide

The title compound was synthesized in a similar manner to Example 66using 2-bromoacetamide.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.52 (2H, s), 6.38 (1H, d, J=9.2 Hz),6.56 (1H, dd, J=1.6, 3.6 Hz), 6.73 (1H, d, J=3.6 Hz), 6.80 (2H, br s),7.19 (1H, br s), 7.24 (1H, dd, J=2.4, 9.2 Hz), 7.62 (1H, br s), 7.63(1H, d, J=2.4 Hz), 7.77 (1H, br), 8.10 (1H, s).

Example 855-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(cyclopropylmethyl)-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using cyclopropylmethyl bromide.

¹H NMR (400 MHz, CDCl₃) δ ppm; 0.36-0.41 (2H, m), 0.58-0.65 (2H, m),1.22-1.33 (1H, m), 3.84 (2H, d, J=7.2 Hz), 5.16 (2H, br s), 6.44 (1H,dd, J=1.6, 3.6 Hz), 6.62 (1H, d, J=9.2 Hz), 6.68 (1H, d, J=3.6 Hz), 7.21(1H, dd, J=2.4, 9.2 Hz), 7.32 (1H, d, J=2.4 Hz), 7.48-7.52 (1H, m), 8.15(1H, s).

Example 865-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-[2-(2-methoxyethoxy)ethyl]-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 1-bromo-2-(2-methoxyethoxy)ethane.

¹H NMR (400 MHz, CDCl₃) δ ppm; 3.27 (3H, s), 3.39-3.46 (2H, m),3.53-3.61 (2H, m), 3.81 (2H, t, J=4.8 Hz), 4.19 (2H, t, J=4.8 Hz), 5.50(2H, br s), 6.43 (1H, dd, J=1.6, 3.2 Hz), 6.59 (1H, d, J=9.2 Hz), 6.66(1H, d, J=3.2 Hz), 7.19 (1H, dd, J=2.4, 9.2 Hz), 7.41 (1H, d, J=2.4 Hz),7.50 (1H, d, J=1.6 Hz), 8.15 (1H, s).

Example 875-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-ethyl-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinoneand ethyl iodide.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.15 (3H, t, J=7.2 Hz), 3.89 (2H, q,J=7.2 Hz), 6.37 (2H, dd, J=0.8, 3.6 Hz), 6.48 (1H, dd, J=0.4, 9.2 Hz),6.53 (2H, dd, J=1.6, 3.6 Hz), 6.87 (2H, br s), 7.27 (1H, dd, J=2.4, 9.2Hz), 7.61 (1H, d, J=2.4 Hz), 7.75 (2H, dd, J=0.8, 1.6 Hz).

Example 885-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-allyl-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinoneand allyl bromide.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.50 (2H, d, J=5.2 Hz), 4.95 (1H, dd,J=1.2, 17.2 Hz), 5.08 (1H, dd, J=1.2, 10.0 Hz), 5.88 (1H, ddt, J=5.2,10.0, 17.2 Hz), 6.43 (2H, dd, J=0.8, 3.6 Hz), 6.52 (1H, dd, J=0.8, 9.2Hz), 6.53 (2H, dd, J=1.6, 3.6 Hz), 6.86 (2H, br s), 7.32 (1H, dd, J=2.4,9.2 Hz), 7.50 (1H, dd, J=0.8, 2.4 Hz), 7.74 (2H, dd, J=0.8, 1.6 Hz).

Example 895-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-propyl-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinoneand propyl iodide.

¹H NMR (400 MHz, CDCl₃) δ ppm; 0.90 (3H, t, J=7.2 Hz), 1.76 (2H, tq,J=7.2, 7.2 Hz), 3.93 (2H, t, J=7.2 Hz), 6.12 (2H, br s), 6.44 (2H, dd,J=1.6, 3.6 Hz), 6.57 (2H, d, J=3.6 Hz), 6.78 (1H, d, J=9.2 Hz), 7.11(1H, d, J=2.4 Hz), 7.24 (1H, dd, J=2.4, 9.2 Hz), 7.53 (2H, dd, J=0.8,1.6 Hz).

Example 905-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-butyl-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinoneand butyl iodide.

¹H NMR (400 MHz, CDCl₃) δ ppm; 0.90 (3H, t, J=7.2 Hz), 1.23-1.34 (2H,m), 1.65-1.74 (2H, m), 3.98 (2H, t, J=-7.2 Hz), 6.50 (2H, dd, J=1.6, 3.6Hz), 6.75 (2H, d, J=3.6 Hz), 6.81 (1H, d, J=9.2 Hz), 7.04 (2H, br s),7.14 (1H, d, J=2.4 Hz), 7.22-7.30 (1H, m), 7.56 (2H, d, J=1.6 HZ).

Example 915-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-(2-butynyl)-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinoneand 1-bromo-2-butyne.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.74 (3H, t, J=2.4 Hz), 4.65 (2H, q,J=2.4 Hz), 6.41 (2H, dd, J=0.8, 3.6 Hz), 6.52 (1H, dd, J=0.4, 9.2 Hz),6.54 (2H, dd, J=2.0, 3.6 Hz), 6.88 (2H, br s), 7.30 (1H, dd, J=2.4, 9.2Hz), 7.62 (1H, dd, J=0.4, 2.4 Hz), 7.75 (2H, dd, J=0.8, 2.0 Hz).

Example 925-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-(2-fluoroethyl)-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinoneand 1-iodo-2-fluoroethane.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.22 (2H, dt, J=4.8, 26.0 Hz), 4.64(2H, dt, J=4.8, 47.6 Hz), 6.38 (2H, dd, J=0.8, 3.6 Hz), 6.52 (2H, dd,J=1.6, 3.6 Hz), 6.52 (1H, d, J=9.2 Hz), 6.87 (2H, br s), 7.30 (1H, dd,J=2.8, 9.2 Hz), 7.59 (1H, d, J=2.8 Hz), 7.74 (2H, dd, J=0.8, 1.6 Hz).

Example 935-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-thienyl)-1,2-dihydro-2-pyridinone

In a reaction vessel,5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone (50 mg,0.197 mmol), thiophene-3-boronic acid (50 mg, 0.393 mmol), and copperacetate (4 mg, 0.0197 mmol) were suspended in N,N-dimethylformamide (3ml). Pyridine (31 mg, 0.393 mmol) was added thereto, followed bystirring at room temperature for 14.5 hours in the air. After thereaction was terminated, the mixture was concentrated and suspended indimethylsulfoxide. Subsequently, the insoluble matters were removed byfiltration and the resulting filtrate was purified by HPLC, to give thetitle compound (34 mg, 51%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.47 (1H, dd, J=0.8, 9.6 Hz), 6.59 (1H,dd, J=1.6, 3.2 Hz), 6.78 (2H, br s), 6.82 (1H, dd, J=0.8, 3.2 Hz), 7.28(1H, dd, J=2.4, 9.6 Hz), 7.35 (1H, dd, J=1.6, 5.2 Hz), 7.61 (1H, dd,J=3.2, 5.2 Hz), 7.71 (1H, dd, J=0.8, 2.4 Hz), 7.78-7.81 (2H, m), 8.23(1H, s).

Example 945-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-phenyl-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 93using phenylboronic acid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.47 (1H, dd, J=0.8, 9.2 Hz), 6.60 (1H,dd, J=1.6, 3.6 Hz), 6.77 (2H, br s), 6.82 (1H, dd, J=0.8, 3.6 Hz), 7.32(1H, dd, J=2.4, 9.2 Hz), 7.40-7.52 (5H, m), 7.62 (1H, d, J=2.4 Hz), 7.81(1H, dd, J=0.8, 1.6 Hz), 8.21 (1H, s).

Example 955-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-[(E)-2-phenyl-1-ethenyl]-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 93using E-phenylethenylboronic acid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.48 (1H, d, J=9.2 Hz), 6.59 (1H, dd,J=1.6, 3.2 Hz)., 6.79-6.84 (3H, m), 7.15 (1H, d, J=15.2 Hz), 7.27 (1H,dd, J=2.4, 9.6 Hz), 7.29 (1H, d, J=7.6 Hz), 7.37 (2H, t, J=7.6 Hz), 7.51(2H, d, J=7.6 Hz), 7.78 (1H, dd, J=0.8, 1.6 Hz), 7.93 (1H, d, J=15.2Hz), 8.06 (1H, d, J=2.4 Hz), 8.25 (1H, s).

Example 961-{4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-4-piperidinecarboxylicacid

In a reaction vessel,ethyl1-{4-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-2-pyridyl}-4-piperidinecarboxylate(59 mg, 0.128 mmol) was suspended in methanol (0.8 ml). A 5N aqueoussodium hydroxide solution (0.2 ml) was added therto, followed bystirring at room temperature for 15 hours. After the reaction wasterminated, the reaction mixture was extracted with ethyl acetate,washed with water and brine, dried over anhydrous sodium sulfate andthen the filtrate was concentrated, to give the title compound (20 mg,36%) as a white solid.

¹H NMR (400 MHz, MeOH-d₄) δ ppm; 1.60-1.73 (2H, m), 1.88-1.96 (2H, m),2.50-2.60 (1H, m), 2.96-3.05 (2H, m), 4.17-4.25 (2H, m), 6.25 (2H, dd,J=0.8, 3.6 Hz), 6.40 (2H, dd, J=2.0, 3.6 Hz), 6.58 (1H, dd, J=1.2, 5.2Hz), 6.78 (1H, br), 7.55 (2H, dd, J=0.8, 2.0 Hz), 8.20 (1H, dd, J=0.8,5.2 Hz).

Example 974-{5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}butyricacid

The title compound was synthesized in a similar manner to Example 96using methyl4-{5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}butanoate.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.89 (2H, tt, J=7.2, 7.2 Hz), 2.21 (2H,t, J=7.2 Hz), 3.91 (2H, t, J=7.2 Hz), 6.37 (1H, d, J=9.2 Hz), 6.56 (1H,dd, J=1.6, 3.6 Hz), 6.70 (1H, d, J=3.6 Hz), 6.79 (2H, br s), 7.22 (1H,dd, J=2.4, 9.2 Hz), 7.65 (1H, d, J=2.4 Hz), 7.74-7.76 (1H, m), 8.15 (1H,s).

Example 98 5-(2-Fluoro-4-pyridyl)-4-(2-furyl)-2-pyrimidinylamine

The title compound was synthesized in a similar manner to ReferenceExample 6 and Example 14 using2-(2-fluoro-4-pyridyl)-1-(2-furyl)-1-ethanone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.59 (1H, dd, J=1.8, 3.6 Hz), 6.81 (1H,dd, J=0.8, 3.6 Hz), 7.06 (2H, br s, 2H), 7.13 (1H, s), 7.18-7.22 (1H,m), 7.70 (1H, dd, J=0.8, 1.8 Hz), 8.21 (1H, d, J=5.2 Hz), 8.27 (1H, s).

Example 994-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

A suspension of 5-(2-fluoro-4-pyridyl)-4-(2-furyl)-2-pyrimidinylamine(3.00 g, 11.70 mmol) in concentrated hydrochloric acid (15 ml)-water (15ml) was stirred at 100° C. for 2 hours. After cooling as it was, thereaction mixture was neutralized with a 5N aqueous sodium hydroxidesolution. The resulting solid was collected by filtration, washed withwater and dried at 60° C. for 22 hours, to give the title compound (2.19g, 70%) as a pale brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 5.93 (1H, dd, J=1.8, 6.8 Hz), 6.26 (1H,d, J=1.8 Hz), 6.59 (1H, dd, J=1.8, 3.4 Hz), 6.82 (1H, dd, J=0.8, 3.4Hz), 6.96 (2H, br s), 7.31 (1H, d, J=6.8 Hz), 7.78 (1H, dd, J=0.8, 1.8Hz), 8.19 (1H, s).

The compounds of Examples 100 to 142 below were synthesized in a similarmanner to Examples 16, 66, and/or 96 using4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone.

Example 1004-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-benzyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 345 (MH⁺).

Example 1014-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-phenethyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 359 (MH⁺).

Example 1024-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-phenylpropyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 373 (MH⁺).

Example 1034-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-fluorobenzyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 363 (MH⁺).

Example 1044-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-fluorobenzyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 363 (MH⁺).

Example 1054-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(4-fluorobenzyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 363 (MH⁺).

Example 1064-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2,4-difluorobenzyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 381 (MH⁺).

Example 1074-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2,5-difluorobenzyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 381 (MH⁺).

Example 1084-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-trifluoromethylbenzyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 413 (MH⁺).

Example 1094-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(4-trifluoromethylbenzyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 413 (MH⁺).

Example 1104-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 269 (MH⁺).

Example 1114-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-ethyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 283 (MH⁺).

Example 1124-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-propyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 297 (MH⁺).

Example 1131-Allyl-4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

MS m/e (ESI) 295 (MH⁺).

Example 1144-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-butenyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 309 (MH⁺).

Example 1157-{4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}heptanenitrile

MS m/e (ESI) 364 (MH⁺).

Example 1164-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-cyclobutylmethyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 323 (MH⁺).

Example 1174-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-fluoropropyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 315 (MH⁺).

Example 1184-{4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}butyronitrile

MS m/e (ESI) 322 (MH⁺).

Example 1194-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(6-chloro-3-pyridylmethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 380 (MH⁺).

Example 1204-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-pyridylmethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 346 (MH⁺).

Example 1214-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-pyridylmethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 346 (MH⁺).

Example 1224-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(4-pyridylmethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 346 (MH⁺).

Example 1234-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-butynyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 307 (MH⁺).

Example 1244-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(4,4,4-trifluorobutyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 365 (MH⁺).

Example 1254-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-methoxyethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 313 (MH⁺).

Example 1264-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-pentynyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 321 (MH⁺).

Example 1274-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-methylallyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 309 (MH⁺).

Example 1284-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-isobutyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 311 (MH⁺).

Example 1294-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-pentenyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 323 (MH⁺).

Example 1304-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-methyl-2-butenyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 323 (MH⁺).

Example 1314-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-methylbutyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 325 (MH⁺).

Example 1324-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(4-methyl-3-pentenyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 337 (MH⁺).

Example 1334-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-propynyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 293 (MH⁺).

Example 1344-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-diethylaminoethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 354 (MH⁺).

Example 1354-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2,2,2-trifluoroethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 337 (MH⁺).

Example 1364-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-fluoroethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 301 (MH⁺).

Example 1374-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(1,2,2,2-tetrafluoroethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 355 (MH⁺).

Example 1384-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2,2-difluoroethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 319 (MH⁺).

Example 1394-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-ethoxyethyl)-1,2-dihydro-2-pyridinone

MS m/e (ESI) 327 (MH⁺).

Example 140 Methyl{4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}acetate

MS m/e (ESI) 327 (MH⁺).

Example 141{4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}aceticacid

MS m/e (ESI) 313 (MH⁺).

Example 1424-{4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}butyricacid

MS m/e (ESI) 341 (MH⁺).

Example 143N1,N1-Diethyl-2-{4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}acetamide

A suspension of{4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}aceticacid (10 mg, 32 μmol), 1-hydroxybenzotriazole (15 mg, 98 μmol),3-(3′-dimethylaminopropyl)-1-ethylcarbodiimide (15 mg, 96 μmol),diethylamine hydrochloride (18 mg, 164 μmol) and triethylamine (22 μl,160 μmol) in N,N-dimethylformamide (1.0 ml) was stirred at roomtemperature for 17 hours. The reaction mixture was diluted with waterand then extracted with ethyl acetate. The organic layer wasconcentrated and then purified by HPLC, to give the title compound (0.73mg, 6%).

MS m/e (ESI) 368 (MH⁺).

Example 144N1-Phenyl-2-{4-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}acetamide

The title compound was synthesized in a similar manner to Example 143using aniline.

MS m/e (ESI) 388 (MH⁺).

Example 1454-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 99using 5-(2-fluoro-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinylamine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.13 (1H, dd, J=1.6, 6.8 Hz), 6.19 (1H,d, J=1.6 Hz), 6.51-6.56 (4H, m), 6.91 (2H, br s), 7.48 (1H, d, J=6.8Hz), 7.74-7.78 (2H, m).

The compounds of Examples 146 to 148 below were synthesized in a similarmanner to Examples 16 or 66 using4-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone.

Example 146

4-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 335 (MH⁺).

Example 1474-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-ethyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 349 (MH⁺).

Example 1484-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-propyl-1,2-dihydro-2-pyridinone

MS m/e (ESI) 363 (MH⁺).

Example 1495-[2-Amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-(3-hydroxypropyl)-1,2-dihydro-2-pyridinone

The title compound was synthesized in a similar manner to Example 66using 5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinoneand 3-iodopropanol.

MS m/e (ESI) 379 (MH⁺).

Example 150 4-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-pyridinecarboxyamide

A suspension of 5-(2-fluoro-4-pyridyl)-4-(2-furyl)-2-pyrimidinylamine(300 mg, 1.17 mmol) and sodium cyanide in dimethylsulfoxide (3 ml) wasstirred at 150° C. for 46 hours. After cooling as it was, the reactionmixture was diluted with ethyl acetate and washed with an aqueoussolution of saturated ammonium chloride twice. The resulting organiclayer was dried over anhydrous sodium sulfate and concentrated. Theresidue was subjected to silica gel plate (developing solvent;dichloromethane:methanol=10:1) and then washed with diethyl ether, togive the title compound (10 mg, 3%) as a colorless solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.40 (1H, dd, J=1.2, 5.2 Hz), 6.51 (1H,d, J=1.2 Hz), 6.54 (1H, dd, J=1.6, 3.4 Hz), 6.60 (1H, dd, J=0.8, 3.4Hz), 6.89 (2H, br s), 7.72 (1H, dd, J=0.8, 1.6 Hz), 8.04 (1H, d, J=5.2Hz), 8.18 (1H, s).

Example 151 5-(2-Methoxy-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 64using methanol.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.88 (3H, s), 6.08 (2H, d, J=3.6 Hz),6.44 (2H, dd, J=1.6, 3.6 Hz), 6.73 (1H, br), 6.87-6.94 (3H, m), 7.65(2H, d, J=1.6 Hz), 8.23 (1H, d, J=5.2 Hz).

Example 152 5-(2-Ethoxy-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 64using ethanol.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.32 (3H, t, J=7.2 Hz), 4.34 (2H, q,J=7.2 Hz), 6.09 (2H, dd, J=0.8, 3.6 Hz), 6.45 (2H, dd, J=1.6, 3.6 Hz),6.70 (1H, dd, J=0.8, 1.2 Hz), 6.88-6.94 (3H, m), 7.67 (2H, dd, J=0.8,1.6 Hz), 8.22 (1H, dd, J=0.8, 5.2 Hz).

Example 153 5-(2-Propoxy-4-pyridyl)-4,6-di(2-furyl)-2-pyrimidinamine

The title compound was synthesized in a similar manner to Example 64using n-propanol.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 0.95 (3H, t, J=7.2 Hz), 1.72 (2H, tq,J=7.2, 7.2 Hz), 4.25 (2H, t, J=7.2 Hz), 6.09 (2H, dd, J=0.8, 3.6 Hz),6.45 (2H, dd, J=1.6, 3.6 Hz), 6.70 (1H, dd, J=0.8, 1.2 Hz), 6.89-6.94(3H, m), 7.67 (2H, dd, J=0.8, 1.6 Hz), 8.22 (1H, dd, J=0.8, 5.2 Hz).

Example 154 5-(6-Chloro-3-pyridyl)-4-(2-thienyl)-2-pyrimidinylamine

The title compound was obtained in a similar manner to Example 14 using2-(6-chloro-3-pyridyl)-3-(dimethylamino)-1-(2-thienyl)-2-propen-1-one.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.73 (1H, dd, J=1.2, 4.0 Hz), 6.94 (2H,br s), 6.98 (1H, dd, J=4.0, 5.0 Hz), 7.59 (1H, dd, J=0.8, 8.2 Hz), 7.67(1H, dd, J=1.2, 5.0 Hz), 7.83 (1H, dd, J=2.4, 8.2 Hz), 8.17 (1H, s),8.36 (1H, dd, J=0.8, 2.4).

Example 155 5-(6-Chloro-3-pyridyl)-4-phenyl-2-pyrimidinylamine

The title compound was obtained in a similar manner to Example 14 using2-(6-chloro-3-pyridyl)-3-(dimethylamino)-1-phenyl-2-propen-1-one.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 7.01 (2H, br s), 7.27-7.40 (5H, m),7.42 (1H, dd, J=0.8, 8.2 Hz), 7.55 (1H, dd, J=2.8, 8.2 Hz), 8.14 (1H,dd, J=0.8, 2.8 Hz), 8.35 (1H, s).

Example 156 5-(6-Chloro-3-pyridyl)-4-(3-fluorophenyl)-2-pyrimidinylamine

The title compound was obtained in a similar manner to Example 14 using2-(6-chloro-3-pyridyl)-3-(dimethylamino)-1-(3-fluorophenyl)-2-propen-1-one.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 7.00-7.06 (1H, m), 7.07 (2H, br s),7.15-7.25 (2H, m), 7.33-7.39 (1H, m), 7.44 (1H, dd, J=0.6, 8.2 Hz), 7.58(1H, dd, J=2.6, 8.2 Hz), 8.18 (1H, dd, J=0.6, 2.6 Hz), 8.38 (1H, s).

The compounds represented by the above formula (I) according to thepresent invention are useful as an adenosine receptor (A₁, A_(2A),A_(2B) or A₃ receptor) antagonist and are specifically useful as anA_(2B) receptor antagonist. Test examples demonstrating the efficacy ofthe compounds of the present invention as a medicament will be describedbelow.

Test Example 1 Measurement of the binding affinity to adenosine A₁receptor

A human adenosine A₁ receptor cDNA was expressed in excess in CHOK1cells, and this membrane sample was suspended at a protein concentrationof 66.7 μg/ml in 20 mM HEPES buffer, pH 7.4 (10 mM MgCl₂, 100 mM NaCl).To 0.45 ml of this membrane sample suspension were added 0.025 ml of 60nM tritium-labeled chlorocyclopentyl adenosine (³H-CCPA, from NEN Ltd.)and 0.025 ml of test compound. This mixture was left at 30° C. for 120minutes, filtered rapidly under suction through a glass fiber filter(GF/B, from Whatman), and immediately washed twice with 5 ml of 50 mMwater-cooled Tris-HCl buffer. Thereafter, the glass fiber filter wastransferred to a vial, scintillator was added thereto, and theradioactivity on the filter was measured by a liquid scintillationcounter. The inhibition of binding of ³H-CCPA to A₁ receptor by the testcompound was determined using the following formula, and from thisvalue, 50% inhibition concentration (IC₅₀) was calculated. Inhibition(%)=[1-{(binding in the presence of the test compound-nonspecificbinding)/(total binding-nonspecific binding)}]×100

In the above formula, the total binding means ³H-CCPA-boundradioactivity in the absence of the test compound; the nonspecificbinding means ³H-CCPA-bound radioactivity in the presence of 100 μM CPA([R]-[1-methyl-2-phenylethyl]adenosine); and the binding in the presenceof the test compound means ³H-CCPA-bound radioactivity in the presenceof the test compound at predetermined concentrations. The inhibitionconstant (Ki value) in the table was determined from the formula ofCheng-Prusoff.

Test Example 2 Measurement of the Binding Ability to Adenosine A_(2A)Receptor

An experiment of inhibition of binding to adenosine A_(2A) receptor wasconducted using a membrane sample (Receptor Biology Inc.) where anadenosine A_(2A) receptor cDNA was expressed in excess. This membranesample was suspended at a protein concentration of 22.2 μg/ml in 20 mMHEPES buffer, pH 7.4 (10 mM MgCl₂ and 100 mM NaCl). To 0.45 ml of thismembrane sample suspension were added 0.025 ml of 500 nM tritium-labeled2-p-[2-carboxyethyl]phenetylamino-5′-N-ethylarboxyamide adenosine(³H-CGS21680, from NEN) and 0.025 ml of test compound. This mixture wasleft at 25° C. for 90 minutes, filtered rapidly under suction through aglass fiber filter (GF/B, from Whatman), and immediately washed twicewith 5 ml of 50 mM ice-cooled Tris-HCl buffer. Thereafter, the glassfiber filter was transferred to a vial, scintillator was added thereto,and the radioactivity on the filter was measured by a liquidscintillation counter. The inhibition of binding of ³H-CGS21680 toA_(2A) receptor by the test compound was determined using the followingformula, and from this inhibition, 50% inhibition concentration (IC₅₀)was calculated.Inhibition (%)=[1−{[(binding in the presence of the testcompound)−(nonspecific binding)]/[(total binding)−(nonspecificbinding)]}]×100

Here, the total binding means ³H-CGS21680-bound radioactivity in theabsence of the test compound; the nonspecific binding means³H-CGS21680-bound radioactivity in the presence of 100 μM RPIA; and thebinding in the presence of the test compound means ³H-CGS21680-boundradioactivity in the presence of the test compound at predeterminedconcentrations. The inhibition constant (Ki value) in the table wasdetermined from the formula of Cheng-Prusoff.

Test Example 3 Experiment of Inhibition of NECA-stimulated Production ofcAMP in Adenosine A_(2B) Receptor-expressing Cells

CHOK1 cells where human adenosine A_(2B) receptor had been expressed inexcess were plated onto a 24-well plate at a density of 1.5×10⁵cells/well, cultured overnight, and used in the experiment. The degreeof inhibitory effect of the test compound on the amount of cAMP producedby stimulation with 30 nM 5′-N-ethylcarboxyamide adenosine (NECA fromSigma) was evaluated in terms of affinity for A_(2B) receptor. That is,the adhering cells were washed twice with 2 ml/well Krebs-Ringer buffersolution (containing 0.1% BSA; pH 7.4) and pre-incubated for 30 minutesin a volume of 0.5 ml/well. Then, a mixed solution containing NECA andthe test compound was added in a volume of 0.1 ml/well in the presenceof a phosphodiesterase inhibitor Ro-20-1724 (a product of RBI). Afterpre-incubation for 15 minutes, the reaction was terminated with 0.1 NHCl in a volume of 300 μl/well. Measurement of intracellular cAMP wascarried out using a cAMP enzyme immunoassay kit produced by Amersham.The inhibition of NECA-stimulated production of cAMP by the testcompound was determined using the following equation:Inhibition (%)=[1−{(amount of cAMP in the coexistence of NECA and thetest compound-amount of cAMP in only the Krebs-Ringer buffersolution)/(amount of cAMP upon stimulation with NECA only-amount of cAMPin only the Krebs-Ringer buffer solution)}]×100

The ability of the compound according to the present invention to bindto or the ability to antagonize adenosine receptor are as follows.

TABLE 1 Ki (nM) Ki (nM) IC₅₀ (nM) Test Compound A₁ A_(2A) A_(2B) Ex 16175 6 29 Ex 17 289 3 25 Ex 18 114 2 26

The compounds according to the present invention, salts thereof orsolvates of them have an excellent inhibitory action against theadenosine receptors.

Test Example 4 Evaluation of Defecation-Promoting Action

The defecation-promoting action of the adenosine A_(2B)receptor-inhibiting compound which was identified by measuring thebinding affinity or antagonistic activity thereof to the adenosinereceptor in Test Examples 1 to 3, a salt thereof, a solvate of them, ora pharmaceutical composition containing it can be evaluated on the basisof the following method. That is, SD IGS rats (6 weeks-old, from CharlesRiver) were placed in cages (3 animals/cage) and preliminarily allowedfood and water ad libitum and raised for 1 week. Then, a taredwater-absorbing sheet was placed below each cage, and the animals werefasted but allowed water ad libitum throughout the experiment. After 1.5hours, the fecal pellets were collected from each cage and observed forabnormality before the experiment. The compound suspended or dissolvedin 0.5% (w/v) methyl cellulose (MC) was orally administered in a volumeof 5 ml/kg. On one hand, 0.5% (w/v) MC only was orally given to thecontrol group. After administration of the compound, the rats werereturned to the cage provided with a new water-absorbing sheet, and 90minutes after the administration, the fecal pellets on thewater-absorbing sheet were collected from each cage, and the externalappearance was observed, and then counted and weighed. The number offecal pellets is expressed per each cage.

TABLE 2 Number of fecal pellets Test Compound Dose Mean ± S.E. Control —1.25 ± 0.63 Ex 16 3 mg/kg 12.50 ± 0.96  Ex 17 3 mg/kg 15.50 ± 3.18  Ex18 3 mg/kg 14.50 ± 1.26 

The compounds according to the present invention, a salt thereof orsolvates of them have an excellent defecation-promoting action.

Test Example 5 Evaluation of Effects on Haloperidol-induced Catalepsy

Parkinson's disease is a disease caused by the degeneration or celldeath of nigrostriatal dopaminergic neurons. The administration ofhaloperidol (dopamine D₁/D₂ receptor antagonist) blocks postsynaptic D₂receptors to induce catalepsy. The haloperidol-induced catalepsy hasbeen known as a classic model that mimics Parkinson's disease by drugadministration (Eur. J. Pharmacol., 182, 327-334(1990)).

The adenosine A_(2A) receptor antagonist compounds identified bymeasuring on their binding abilities to the receptors in Test Examples 1to 3, the salts thereof, solvates of them, or pharmaceuticalcompositions containing those were evaluated for effect onhaloperidol-induced catalepsy by the method described below. That is,the experiment was conducted by eight 5-week-old male ICR mice(available from Charles River) per group. Haloperidol (manufactured bySigma Co., Ltd.) was dissolved in a 6.1% tartaric acid solution and theresulting solution in a dose of 1 mg/kg was then intraperitoneallyadministered to the mice. The test compound was used as a 0.5% MCsuspension. 1.5 hours after the intraperitoneal administration ofhaloperidol, each of the suspension with the test compound and thesuspension without the test compound (control) was orally administeredto the mice (0.1 ml per 10 g of mouse body weight). 1 hour after theadministration of the test compound, the degree of catalepsy wasmeasured with respect to each of the mice such that a pair of onlyforelimbs and a pair of only hindlimbs of each mouse were placed byturns on a stand 4.5 cm in height and 10 cm in width. 0.1 mg/kg and 0.3mg/kg of each of the test compounds were orally administered. Catalepsyscores and criterions are as follows.

Score Duration of catalepsy

-   0: When the pair of only forelimbs and the pair of only hindlimbs    are independently placed on the stand, the duration of such a    posture of each pair for less than 5 seconds.-   1: The duration of the posture in which the forelimbs were being    placed on the stand was 5 or more seconds but less than10 seconds,    and the duration of such a posture of the hindlimbs was less than 5    seconds.-   2: The duration of the posture in which the forelimbs were being    placed on the stand was 10 or more seconds, and the duration of such    a posture of the pair hindlimbs was less than 5 seconds.-   3: The duration of the posture in which both the forelimbs and    hindlimbs were being placed on the stand was 5 or more seconds but    less than 10 seconds; or the duration of the posture in which the    forelimbs were being placed on the stand was less than 5 seconds and    the duration of such a posture of the hindlimbs was 5 or more    seconds.-   4: The duration of the posture in which the forelimbs were being    placed on the stand was 10 or more seconds and the duration of such    a posture of the hindlimbs was 5 or more seconds but less than 10    seconds; or the duration of the posture in which the forelimbs were    being placed on the stand was 5 or more seconds but less than 10    seconds and the duration of such a posture of the hindlimbs was 10    or more seconds.-   5: The duration of the posture in which both the forelimbs and    hindlimbs were being placed on the stand was 10 or more seconds.

The effects of the compound were determined by making a comparisonbetween the score of the control group and the score of the test groupin which the test compound was administered. A significant differencewas analyzed by Dunnett's-test. The results are shown in Table 3.

TABLE 3 Administered Dose of Catalepsy score Name of group content TestCompound (Mean ± S.E.) Control Haloperidol 5.00 ± 0.00 Example 16Haloperidol + 0.1 mg/kg 4.63 ± 0.38 Test compound Example 16Haloperidol + 1.0 mg/kg 0.88 ± 0.64** Test compound Example 17Haloperidol + 0.1 mg/kg 3.38 ± 0.53** Test compound Example 17Haloperidol + 1.0 mg/kg 1.13 ± 0.67** Test compound **p < 0.01(comparison with Control group)

1. A compound represented by the following formula (I), a salt thereofor a solvate thereof:

in the formula, R¹ and R² are the same as or different from each otherand each represents a hydrogen atom, an alkyl group having one to sixcarbon atoms which may be substituted, an alkenyl group having two tosix carbon atoms which may be substituted, an alkynyl group having twoto six carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, anaromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted, an acyl group having one to six carbon atomswhich may be substituted or an alkylsulfonyl group having one to sixcarbon atoms which may be substituted; R³ represents a hydrogen atom, ahalogen atom, a cyano group, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, an aromatic hydrocarboncyclic group having six to fourteen carbon atoms which may besubstituted, a nitrogen atom which may be substituted, an oxygen atomwhich may be substituted or a sulfur atom which may be substituted; R⁴is a group represented by the formula (V):

wherein R⁸ represents a group selected from the following substituentgroup a; and the ring B may be substituted with one to four groupsselected from the following substituent group a: Substituent group a thegroup consisting of a hydrogen atom, a halogen atom, a hydroxyl group, anitro group, a cyano group, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, an alkoxy group having one tosix carbon atoms which may be substituted, an alkenyloxy group havingtwo to six carbon atoms which may be substituted, an alkynyloxy grouphaving two to six carbon atoms which may be substituted, an alkylthiogroup having one to six carbon atoms which may be substituted, analkenylthio group having two to six carbon atoms which may besubstituted, an alkynylthio group having two to six carbon atoms whichmay be substituted, an aliphatic acyl group having two to seven carbonatoms, a carbamoyl group which may be substituted, an arylacyl group, anamino group which may be substituted, an alkylsulfonyl group having oneto six carbon atoms which may be substituted, an alkenylsulfonyl grouphaving two to six carbon atoms which may be substituted, analkynylsulfonyl group having two to six carbon atoms which may besubstituted, an alkylsulfinyl group having one to six carbon atoms whichmay be substituted, an alkenylsulfinyl group having two to six carbonatoms which may be substituted, an alkynylsulfinyl group having two tosix carbon atoms which may be substituted, a formyl group, a cycloalkylgroup having three to eight carbon atoms which may be substituted, acycloalkenyl group having three to eight carbon atoms which may besubstituted, and an aromatic hydrocarbon cyclic group having six tofourteen carbon atoms which may be substituted; and R⁵ represents anaromatic hydrocarbon cyclic group having six to fourteen carbon atomswhich may be substituted or furyl which may be substituted.
 2. Apharmaceutical composition comprising the compound according to claim 1,a salt thereof or a solvate thereof.
 3. A method for promotingdefecation, which comprises administering a pharmacologically effectiveamount of the compound according to claim 1, a salt thereof or a solvatethereof to a patient in need thereof.
 4. A compound selected from thegroup consisting of: (1)5-(2-amino-4-(2-furyl)-5-pyrimidinyl-1-methyl-1,2-dihydro-2-pyridinone;(2)5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1-ethyl-1,2-dihydro-2-pyridinone;(3)1-allyl-5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone;(4)5-[2-amino-4-(3-fluorophenyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone;(5)5-(2-amino-4-phenyl-5-pyrimidinyl)-1-methyl-1,2-dihydro-2-pyridinone;(6)5-[2-amino-4,6-di(2-furyl)-5-pyrimidinyl]-1-methyl-1,2-dibydro-2-pyridinone;and (7)5-[2,4-diamino-6-(3-fluorophenyl)-5-pyrimidinyl]-1-methyl-1,2-dihydro-2-pyridinone,and a salt or a solvate thereof.
 5. The compound according to claim 1, asalt thereof or a solvate thereof, wherein R¹ mid R² are hydrogen atoms.6. The Compound according to claim 1, a salt thereof or a solvatethereof, wherein R³ represents a hydrogen atom, an amino group, a cyanogroup, or an alkyl group having one to six carbon atoms, an alkoxylgroup having one to six carbon atoms, phenyl, or naphthyl, each of whichmay be substituted.
 7. The compound according to claim 1, a salt thereofor a solvate thereof, wherein R³ is a hydrogen atom.
 8. The compoundaccording to claim 1, a salt thereof or a solvate thereof, wherein R⁵represents a phenyl, 2-furyl or 3-furyl, each of which may besubstituted.
 9. The compound according to claim 1, a salt thereof or asolvate thereof, wherein R⁵ represents a phenyl, or 2-furyl, each ofwhich, may be substituted.
 10. The compound according to claim 1, a saltthereof or a solvate thereof, wherein the Substituent group a consistsof a hydrogen atom, a halogen atom, an alkyl group having one to sixcarbon atoms which may be substituted, an alkenyl group having two tosix carbon atoms which may be substituted, an alkynyl group having twoto six carbon atoms which may be substituted, an alkoxy group having oneto six carbon atoms which may be substituted, a carbamoyl group whichmay be substituted, and an amino group which may be substituted.
 11. Amethod for treating Parkinson's disease or depression comprisingadministering a pharmacologically effective amount of a compoundaccording to claim 1, a salt thereof or a solvate thereof, to a patientin need thereof.
 12. A method for treating constipation comprisingadministering a pharmacologically effective amount of a compoundaccording to claim 1, a salt thereof or a solvate thereof, to a patientin need thereof.
 13. The method of claim 12, wherein the constipation isfunctional constipation.
 14. A method for treating irritable bowelsyndrome, constipation accompanying irritable bowel syndrome, organicconstipation, constipation accompanying enteroparalytic ileus,constipation accompanying congenital digestive tract dysfunction orconstipation accompanying ileus comprising administering apharmacologically effective amount of a compound according to claim 1, asalt thereof or a solvate thereof, to a patient in need thereof.
 15. Amethod for evacuating intestinal tracts at the time of examination ofdigestive tracts or before and alter an operation comprisingadministering a pharmacologically effective amount of a compoundaccording to claim 1, a salt thereof or a solvate thereof, to a patientin need thereof.
 16. A compound selected from the group consisting of:(1)5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-fluoroethyl)-1,2-dihydro-2-pyridinone;(2)5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(8-hydroxyoctyl)-1,2-dihydro-2-pyridinone;(3) Methyl4-{5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}butanoate;(4)5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-propynyl)-1,2-dihydro-2-pyridinone;(5)5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-isobutyl-1,2-dihydro-pyridinone;(6)5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-butynyl)-1,2-dihydro-2-pyridinone;(7)5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-benzyl-1,2-dihydro-2-pyridinone;(8)5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-isopenty1-1,2-dihydro-2-pyridinone;(9)5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-methylbutyl)-1,2-dihydro-2-pyridinone;(10)5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-octyl-1,2-dihydro-2-pyridinone;(11)2-{5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}ethylcyanide;(12)5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-fluoropropyl)-1,2-dihydro-2-pyridinone;(13)5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-hydroxyethyl)-1,2dibydro-2-pyridinone;(14)5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-hydroxypropyl)-1,2-dihydro-2-pyridinone;and (15)5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-methoxyethyl)-1,2-dihydro-2-pyridinone;and a salt or a solvate thereof. 17.5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-fluoroethyl)-1,2-dihydro-2-pyridinone,a salt thereof or a solvate thereof. 18.5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(8-hydroxyoctyl)-1,2-dihydro-2-pyridinone,a salt thereof or a solvate thereof.
 19. Methyl4-{5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}butanoate,a salt thereof or a solvate thereof. 20.5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-propynyl)-1,2-dihydro-2-pyridinone,a salt thereof or a solvate thereof. 21.5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-isobutyl-1,2-dihydro-pyridinone,a salt thereof or a solvate thereof. 22.5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-butynyl)-1,2-dihydro-2-pyridinone,a salt thereof or a solvate thereof. 23.5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-benzyl-1,2-dihydro-2-pyridinone,a salt thereof or a solvate thereof. 24.5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-isopentyl-1,2-dihydro-2-pyridinone,a salt thereof or a solvate thereof. 25.5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-methylbutyl)-1,2-dihydro-2-pyridinone,a salt thereof or a solvate thereof. 26.5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-octyl-1,2-dihydro-2-pyridinone,a salt thereof or a solvate thereof. 27.2-{5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-2-oxo-1,2-dihydro-1-pyridinyl}ethylcyanide,a salt thereof or a solvate thereof. 28.5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-fluoropropyl)-1,2-dihydro-2-pyridinone,a salt thereof or a solvate thereof. 29.5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-hydroxyethyl)-1,2-dihydro-2-pyridinone,a salt thereof or a solvate thereof. 30.5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(3-hydroxypropyl)-1,2-dihydro-2-pyridinone,a salt thereof or a solvate thereof. 31.5-[2-Amino-4-(2-furyl)-5-pyrimidinyl]-1-(2-methoxyethyl)-1,2-dihydro-2-pyridinone,a salt thereof or a solvate thereof.
 32. A method for antagonizing anadenosine A₂ receptor in vitro comprising administering a compoundaccording to claim 1, a salt thereof or a solvate thereof, to anadenosine A₂ receptor in vitro.
 33. A method for antagonizing anadenosine A_(2A) receptor in vitro comprising administering a compoundaccording to claim 1, a salt thereof or a solvate thereof, to anadenosine A_(2A) receptor in vitro.
 34. A method for antagonizing anadenosine A_(2B) receptor in vitro comprising administering a compoundaccording to claim 1, a salt thereof or a solvate thereof to anadenosine A_(2B) receptor in vitro.